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

Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications

The discovery of cardiac natriuretic hormones required a profound revision of the concept of heart function. The heart should no longer be considered only as a pump, but rather as a multi-functional and interactive organ, part of a complex network and active component of the integrated systems of the body. In the present review, we will first consider the cross-talk between endocrine and contractile function of the heart. Then, based on the existing literature, we will propose the hypothesis that cardiac endocrine function is an essential component of the integrated systems of the body and thus plays a pivotal role in fluid, electrolyte and hemodynamic homeostasis. We will highlight those studies indicating how alterations in cardiac endocrine function can better explain the pathophysiology of cardiovascular diseases and in particular of heart failure, in which several target organs develop a resistance to the biological action of cardiac natriuretic peptides. Finally, we will emphasize the concept that a complete knowledge of the cardiac endocrine function and of its relation with other neurohormonal regulatory systems of the body is crucial to correctly interpret changes in circulating natriuretic hormones, especially the brain natriuretic peptide

REGIONAL MAPPING OF MYOCARDIAL HIBERNATION PHENOTYPE IN IDIOPATHIC END-STAGE DILATED CARDIOMYOPATHY

Myocardial hibernation (MH) is a well-known feature of human ischaemic cardiomyopathy (ICM), whereas its presence in human idiopathic dilated cardiomyopathy (DCM) is still controversial. We investigated the histological and molecular features of MH in left ventricle (LV) regions of failing DCM or ICM hearts. We examined failing hearts from DCM (n = 11; 41.9 ± 5.45 years; left ventricle-ejection fraction (LV-EF), 18 ± 3.16%) and ICM patients (n = 12; 58.08 ± 1.7 years; LVEF, 21.5 ± 6.08%) undergoing cardiac transplantation, and normal donor hearts (N, n = 8). LV inter-ventricular septum (IVS) and antero-lateral free wall (FW) were transmurally (i.e. sub-epicardial, mesocardial and sub-endocardial layers) analysed. LV glycogen content was shown to be increased in both DCM and ICM as compared with N hearts (P < 0.001), with a U-shaped transmural distribution (lower values in mesocardium). Capillary density was homogenously reduced in both DCM and ICM as compared with N (P < 0.05 versus N), with a lower decrease independent of the extent of fibrosis in sub-endocardial and sub-epicardial layers of DCM as compared with ICM. HIF1-α and nestin, recognized ischaemic molecular hallmarks, were similarly expressed in DCM-LV and ICM-LV myocardium. The proteomic profile was overlapping by ~50% in DCM and ICM groups. Morphological and molecular features of MH were detected in end-stage ICM as well as in end-stage DCM LV, despite epicardial coronary artery patency and lower fibrosis in DCM hearts. Unravelling the presence of MH in the absence of coronary stenosis may be helpful to design a novel approach in the clinical management of DCM

Glucose-6-phosphate dehydrogenase-derived NADPH fuels superoxide production in the failing heart.

In the failing heart, NADPH oxidase and uncoupled NO synthase utilize cytosolic NADPH to form superoxide. NADPH is supplied principally by the pentose phosphate pathway, whose rate-limiting enzyme is glucose 6-phosphate dehydrogenase (G6PD). Therefore, we hypothesized that cardiac G6PD activation drives part of the excessive superoxide production implicated in the pathogenesis of heart failure. Pacing-induced heart failure was performed in eight chronically instrumented dogs. Seven normal dogs served as control. End-stage failure occurred after 28 +/- 1 days of pacing, when left ventricular end-diastolic pressure reached 25 mm Hg. In left ventricular tissue homogenates, spontaneous superoxide generation measured by lucigenin (5 microM) chemiluminescence was markedly increased in heart failure (1338 +/- 419 vs. 419 +/- 102 AU/mg protein, P < 0.05), as were NADPH levels (15.4 +/- 1.5 vs. 7.5 +/- 1.5 micromol/gww, P < 0.05). Superoxide production was further stimulated by the addition of NADPH. The NADPH oxidase inhibitor gp91(ds-tat) (50 microM) and the NO synthase inhibitor L-NAME (1 mM) both significantly lowered superoxide generation in failing heart homogenates by 80% and 76%, respectively. G6PD was upregulated and its activity higher in heart failure compared to control (0.61 +/- 0.10 vs. 0.24 +/- 0.03 nmol/min/mg protein, P < 0.05), while superoxide production decreased to normal levels in the presence of the G6PD inhibitor 6-aminonicotinamide. We conclude that the activation of myocardial G6PD is a novel mechanism that enhances NADPH availability and fuels superoxide-generating enzymes in heart failure

Hyaluronan mixed esters of butyric and retinoic acid drive cardiac and endothelial fate in term placenta human mesenchymal stem cells and enhance cardiac repair in infarcted rat hearts.

We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as a novel cardiogenic/vasculogenic agent in human mesenchymal stem cells isolated from bone marrow, dental pulp, and fetal membranes of term placenta (FMhMSCs). HBR remarkably enhanced vascular endothelial growth factor (VEGF), KDR, and hepatocyte growth factor (HGF) gene expression and the secretion of the angiogenic, mitogenic, and antiapoptotic factors VEGF and HGF, priming stem cell differentiation into endothelial cells. HBR also increased the transcription of the cardiac lineage-promoting genes GATA-4 and Nkx-2.5 and the yield of cardiac markerexpressing cells. These responses were notably more pronounced in FMhMSCs. FMhMSC transplantation into infarcted rat hearts was associated with increased capillary density, normalization of left ventricular function, and significant decrease in scar tissue. Transplantation of HBR-preconditioned FMhM-SCs further enhanced capillary density and the yield of human vWF-expressing cells, additionally decreasing the infarct size. Some engrafted, HBR-pretreated FMhMSCs were also positive for connexin 43 and cardiac troponin I. Thus, the beneficial effects of HBR-exposed FMhMSCs may be mediated by a large supply of angiogenic and antiapoptotic factors, and FMhMSC differentiation into vascular cells. These findings may contribute to further development in cell therapy of heart failure

Detection of 3D Cardiac metabolism after injection of hyperpolarized [1-13C]pyruvate

Introduction MRI with hyperpolarised 13C represents a promising modality for in-vivo spectroscopy and provides a unique opportunity for non-invasive assessment of cardiac regional metabolism. Purpose We present a method based on a volumetric IDEAL spiral CSI acquisition for obtaining spatial information on the metabolism of the whole heart after intravenous injection of hyperpolarized [1-13C]pyruvate in a large animal model with a clinical 3T scanner. Methods Three healthy male mini-pigs (38±2 kg) were maintained under deep sedation; a dose of 20 mL of 230 mM [1-13C]pyruvate was administered over about 10 s by manual injection. Animal experiments were performed on a 3T GE Signa HDx scanner with a 13C quadrature birdcage coil. [1-13C]pyruvate was polarized using a HyperSense DNP polariser with subsequent dissolution. The final injection solution contained 230 mM sodium [1-13C]pyruvate, 100 mM TRIS buffer, 0.27 mM Na2EDTA and 20 μM Dotarem with T≈37°C and pH ≈ 7.6. Anatomical reference images were acquired in the axial plane with standard FIESTA sequence (body coil FOV=30x30 cm2, FA=20°, TE/TR=3.8ms/7.52ms, matrix 224x160, slice thickness 5 mm, 20 slices). Metabolic information covering the heart were obtained using a 3D IDEAL spiral CSI prescribed on the same region imaged by the reference anatomical sequence (FOV= 30x30 cm, slab thickness=100mm) starting 20 seconds after the beginning of the hyperpolarized [113C]-pyruvate injection. The IDEAL spiral CSI concept was implemented into a multi-slice, pulse-and-acquire sequence with a 2D spiral readout and phase encoding along the third dimension. A constant echo time shift of TE=0.9ms, 11 encoding steps and FA=7° were used to optimize the study for the considered frequencies. The data was reconstructed using spectrally-preconditioned, minimum-norm CS inversion followed by gridding reconstruction implemented in Matlab. The reconstruction on cardiac short axis (SA) and image fusion was performed by PMOD software. Results Pyruvate and its metabolic products lactate and bicarbonate were detected in the heart. Metabolic maps overlaid on anatomical images are shown in Figure 1. On SA sections the metabolites signal resulted correctly localized in cardiac structures: pyruvate more evident in ventricular cavity, bicarbonate in myocardial wall

Metabolic alterations induce oxidative stress in diabetic and failing hearts: different pathways, same outcome

Several authors have proposed a link between altered cardiac energy substrate metabolism and reactive oxygen species (ROS) generation. A cogent evidence of this association has been found in diabetic cardiomyopathy (dCM); however, experimental findings in animal models of heart failure (HF) and in human myocardium also seem to support the coexistence of the two alterations in HF

Animal models of dilated cardiomyopathy for translational research.

Animal models of cardiovascular disease have proved critically important for the discovery of pathophysiological mechanisms and for the advancement of diagnosis and therapy. They offer a number of advantages, principally the availability of adequate healthy controls and the absence of confounding factors such as marked differences in age, concomitant pathologies and pharmacological treatments. Dilated cardiomyopathy (DCM) is the third cause of heart failure (HF) and is characterized by progressive ventricular dilation and functional impairment in the absence of coronary lesions and/or hypertension. Over the past thirty years, investigators have developed numerous small and large animal models to study this very complex syndrome. Genetically modified mice are the most widely and intensively utilized research animals and allow high throughput studies on DCM. However, to translate discoveries from basic science into medical applications, research in large animal models becomes a necessary step. An accurate large animal model of DCM is pacing-induced HF. It is obtained by continuous cardiac pacing at a frequency three- to fourfold higher than the spontaneous heart rate and is mostly applied to dogs, but also to pigs, sheep and monkeys. To date, this model can still be considered a gold standard in HF research