**5. Cardiac metabolism**

Normal heart requires a continuous supply of energy to maintain muscle contraction as well as hemodynamic adaptation, survival, growth and metabolism. Neuro-hormonal activation is an important input for cardiovascular response to metabolic demands. Although initially adaptive, neuro-hormonal activation together with metabolic alterations has deleterious effects on cardiovascular system.

In the heart muscle, ATP production is crucial for all cellular and contractile process. In the adult heart, ATP comes mainly from the β-oxidation of fatty acids, an oxygen dependent process. The 10 – 40% remaining come from glucose degradation through glycolysis, an oxygen independent process (Neglia et al., 2007; Stanley et al., 2005).

β-oxidation depends upon fatty acids uptake, which occurs through different fatty acid translocases located in the plasma membrane, like CD36 protein. Fatty acids must be transported to the mitochondria for β-oxidation, which occurs through the enzyme carinitine palmitoyl transferase-1 (CPT-1). Once inside mitochondria, fatty acids are oxidized to produce acetil–CoA, which will be incorporated into Krebs cycle for NADH, FADH2 and CO2 production. These intermediates provide oxidative power during the oxidative phosphorylation in mitochondria, where ATP is finally produced by ATP synthase complex V.

as gender differences in cardiac remodelling. Heart size of men is bigger than women, even when is corrected for body weight. Men also have higher incidence of fibrosis; however direct effects of androgens are not clear. The increase in cardiac mass is higher in men from puberty and has been shown that estrogens have preventive effects on cardiac hypertrophy (Weinberg et al., 1999). In castrated mice, administration of androgen receptor antagonists does not abolish the sex differences in heart size or cardiac fibrosis (Li et al, 2004), suggesting that androgens are not the only determinants for these differences. Negative consequences of fibrosis are mediated mainly by local effect of the renin-angiotensin system. Angiotensin II regulates differentiation and proliferation of ventricular fibroblasts and synthesis of extracellular matrix, which consist mainly of collagen type I and III (Krenning et al., 2010). The synthesis of collagen type I and III by fibroblasts is stimulated by TGF-β1 and inhibited by androgens (Ikeda et al., 2005). Cardiac fibroblasts express androgen receptor, which suggest a role for androgens during cardiac remodelling. Experimental evidence in androgen receptor knockout (ARKO) mice show reduced ventricular volume and wall thickness, but no differences in blood pressure or heart rate as compared with normal animals (Ikeda et al., 2005). It has also been demonstrated that dihydrotestosterone increase atrial natriuretic peptide (ANP) secretion from neonatal rat cardiomyocytes (Marsh et al., 1998). Furthermore, ARKO mice show a significant reduction in ANP gene transcription, resulting in increased cardiac fibrosis. On the other hand, testosterone has been shown to increase the amount of collagen measured around coronary blood vessels contributing to fibrosis in male hypertensive rats independent of the reninangiotensin system. Cavasin et al. (2006) have determined that high testosterone levels enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodelling (Cavasin et al., 2006). Even when the evidence is still controversial, androgens show a protective role on cardiac remodelling and protect the heart from maladaptive fibrosis, preventing the deleterious effects of increased pre- and after-load

Normal heart requires a continuous supply of energy to maintain muscle contraction as well as hemodynamic adaptation, survival, growth and metabolism. Neuro-hormonal activation is an important input for cardiovascular response to metabolic demands. Although initially adaptive, neuro-hormonal activation together with metabolic alterations has deleterious

In the heart muscle, ATP production is crucial for all cellular and contractile process. In the adult heart, ATP comes mainly from the β-oxidation of fatty acids, an oxygen dependent process. The 10 – 40% remaining come from glucose degradation through glycolysis, an

β-oxidation depends upon fatty acids uptake, which occurs through different fatty acid translocases located in the plasma membrane, like CD36 protein. Fatty acids must be transported to the mitochondria for β-oxidation, which occurs through the enzyme carinitine palmitoyl transferase-1 (CPT-1). Once inside mitochondria, fatty acids are oxidized to produce acetil–CoA, which will be incorporated into Krebs cycle for NADH, FADH2 and CO2 production. These intermediates provide oxidative power during the oxidative phosphorylation in mitochondria, where ATP is finally produced by ATP

oxygen independent process (Neglia et al., 2007; Stanley et al., 2005).

induced by angiotensin II.

**5. Cardiac metabolism** 

effects on cardiovascular system.

synthase complex V.

On the other hand, glycolysis requires glucose uptake, which occurs through the glucose transporters 1 and 4 (GLUT1 and GLUT4), the main glucose transporters in cardiac cells. Once inside the cell, the enzymes hexokinase and phosphofructokinase, the glycolysis pacemaker enzyme, lead the conversion of glucose to pyruvate. Through this process 2 ATP molecules are generated from each glucose molecule incorporated.

However, the heart muscle is able to modify the ratio between β-oxidation and glycolysis in response to pro-hypertrophic agents (Stanley et al., 2005). For example, cardiac hypertrophy due to pressure overload is accompanied of a reduction in β-oxidation and an increase in the glycolytic rate as a compensatory mechanism that improves ATP production in the heart muscle (van der Vusse et al., 2000, 2002). In contrast, individuals with uncompensated diabetes usually develop a different cardiac hypertrophy, known as diabetic cardiomyopathy. Since diabetic patients are not able to metabolize glucose, diabetic cardiomyopathy is characterized by an increase in the fatty acids assimilation by cardiac cells, which carry cardiac lipotoxicity (van der Vusse et al., 2000).

During heart failure, cardiac muscle is not able to produce enough ATP for cardiac contraction, resulting in poor contractile performance. It is common to observe heart failure in pathologies associated to bad glucose handling for ATP production, as insulin resistance and diabetes. Metabolic syndrome, which comprehends both pathologies, has been correlated with low testosterone blood levels (Saad & Gooren, 2009, 2011). It has been recently postulated that decrease in testosterone is a link between metabolic syndrome and heart failure. Clinical trials have demonstrated that the administration of testosterone at physiological concentrations improved insulin sensitivity, reduced glycaemia and central obesity, and heart failure progression in men suffering metabolic syndrome (Cook & Romashkan, 2011). In addition to clinical trials, there are new studies related to testosterone effects on glucose metabolism. It has been described that testosterone is necessary to maintenance insulin and glucose concentration in blood. Recent reports have shown an important role for testosterone in the mobilization of glucose transporter GLUT4 to the plasma membrane in skeletal muscle, liver and fat tissue (Muthusamy et al., 2007, 2009).

In spite, elevated testosterone administration in humans is usually associated with the development of cardiac hypertrophy and heart failure; there are several studies that examine the relationship between the testosterone supplementation and heart failure with non positive correlation between them. Nowadays, several clinical trials lead to propose that testosterone supplementation at physiological doses could be a treatment for men with metabolic syndrome and heart failure (Pugh et al., 2000). The effect of testosterone as a metabolic modulator could improve insulin sensitivity and glucose uptake in the heart, which could lead to an increase in ATP production when cardiac output increases. However, evidences about the metabolic properties of testosterone on heart muscle come from observational studies. Research on the molecular mechanisms implicated in the metabolic testosterone actions is required.
