**5. Myocardial metabolism in heart failure**

Developing heart failure leads to decreased flexibility of myocardial metabolism. On the certain stages, HF has a tendency to switch FFA utilization as the main energy substrate to glucose oxidation. Decreased FFA consumption, depleted FFA oxidation enzymes, and mitochondrial oxidation biomarkers characterize this stage. This switch is usually early noted. In experiments, it was admitted that metabolic changes in rat myocardium are found in the second week after artificial aortic constriction, while decreased contractility presented only on the 20th week after bandage [24]. Some researchers say that glycolysis predomination is a marker of terminal myocardial metabolism dysfunction. These changes are associated with adaptation because glycolysis demands 12% less oxygen to produce same the amounts of ATP, then FFA oxidation [3, 79].

Transition to glycolysis promotes increased glucose consumption and raised GLUT 1 expression. In parallel, glucose oxidation is also altered, which leads to uncoupling of glycolysis and glucose oxidation. The combination of depressed FFA utilization and glucose oxidation shows decreased mitochondrial oxidative potential ГЛЮТ1 [87, 110].

During glycolysis and glucose oxidation uncoupling, due to PDH inhibition by PDK, pyruvate is not transported to the mitochondria but metabolized to lactate by LDH. This leads to cellular acidosis, and, by the way, this anaerobic glucose utilization gives only two molecules of ATP (while aerobic—32) [103]. Described changes promote cardiomyocyte hypertrophy, energy metabolism depression, ionic pump dysfunction, Ca+2 accumulation, decreased contractility, apoptosis, and fibrosis. It should be noted that this pattern of myocardial dysfunction development is the same for all cardiomyocytes; even in cases of pulmonary hypertension and compensatory hypertrophy of the right heart, metabolic alterations will be identical to the changes observed in the left heart failure [129].

In available data is also admitted that heart failure promotes myocardial tissue insulin resistance, partially due to neurohormonal remodeling, and is an independent predictive factor of sudden heart death in humans [23, 116]. Insulin resistance leads to decreased glucose utilization and ATP production [116, 169]. In some data, it was elucidated that the TG accumulation in muscles (found by 1H NMR method) promotes insulin resistance [81]. The dependence between TG accumulation and

insulin resistance is explained by Randle' cycle: high FFA intracellular accumulation promotes raised acetyl-CoA/CoA and NADH/NAD ratios, which inhibits PDH and leads to citrate accumulation and phosphofructokinase inhibition. Associated G6P accumulation inhibits HX2, promoting intracellular glucose accumulation and decreasing intracellular glucose transport.

Insulin resistance also can be associated with high circulating insulin concentrations. Adrenergic hyperactivity, concomitant to heart failure, leads to increased glucose mobilization, hormone circulation, and insulin synthesis, lipomobilization due to catecholamines (noradrenaline). Insulin stimulates GLUT 4 and CD36 exocytosis, on the first stages it helps to produce enough ATP from glycolysis and oxidative phosphorylation. But insulin receptors have variable action mechanism. Insulin receptors have two places of connection for insulin. One of them has high affinity to hormone and promotes fast response to insulin stimulation; another is a "slow" one and is activated in cases of high insulin concentration and due to geometrical conformation partially blocks the "fast" part of the receptor. In general, insulin resistance is based on the blockade of all "fast" receptors, increased insulin concentration, and fixation of the hormone on "slow" locus of the insulin receptor [9, 11, 13, 14, 94, 116, 152, 175, 190]. Also, a high concentration of circulating FFA decreases insulin-stimulated GLUT 4 translocation. This can be explained by inhibition of Pi 3 kinase of IR-1, which phosphorylation is decreased by TG and phospholipid (FFA-acetyl-CoA, diacylglycerol, ceramides) accumulation in the cytoplasm [26]. GLUT 1 increased expression also takes a part in this process. Increased glucose flux from GLUT 1 promotes decreased GLUT 4 exocytosis and increased GLUT 4 tissue concentration. Developing GLUT 4 function reduction pathological cardiomyocyte hypertrophy and systolic dysfunction occurs [92, 177, 188]. Another factor is pyruvate utilization in anaplerotic reactions, which leads to decreased acetyl-CoA production for Kreb's cycle, glycolysis and oxidative phosphorylation uncoupling, and PDK 4 activation (promotes inhibition of insulin-stimulated glycolysis) [133].

Also it should be noted that in diabetes and insulin resistance, HX2 activity is decreased. In cell culture experiments, it was found that insulin is HX2 gene expression and protein resynthesis regulator. So, the severity of insulin resistance is a suppressor of HX2 function, leading to G6P accumulation and cytoplasm protein glycosylation. It should be admitted that decreased HX2 microRNA is associated with GLUT 4 genes and protein depletion. These interactions between insulin, HX2, and GLUT can be controlled by insulin sensibilization—by thiazolidinediones (pioglitazone, troglitazone) [124, 132].

Often heart failure is accompanied by all energy-producing enzyme dysfunction. Significant reduction of activity is noted in creatine kinase (CK) function. This enzyme regulates transfer between ATP and creatine. CK is a dimer and consists of two parts M and B, and there are three isoforms: MM, BB, MB, and mitochondrial-CK [193]. MM-CK is closely connected with SR and coupled with Ca+2-ATPase, producing energy for Ca+2 circulation [182]. Mitochondrial-CK is located on the inner membrane of the mitochondria and works with the ADP-ATP translocator. Produced ATP is transported by translocator to mitochondrial-CK and further to creatine phosphate or ADP. This compartment distribution provides effective control of local ATP/ADP ratio and promotes mitochondrial ATP production (decreased ratio) or increases enzymes activity. But in conditions of cardiomyopathy, the normal compartment system is altered. Decompartmentalization leads to uncoupling of the mitochondria—mitochondrial-CK-ATP and phosphocreatine interactions [29, 176].

One experimental research elucidated CK activity in rats with induced heart failure. General CK activity was decreased to 45% from normal value; in particular,

**71**

*Myocardial Metabolism*

damage [4, 65].

*DOI: http://dx.doi.org/10.5772/intechopen.80870*

its oxidative function is upregulated [184].

marker of decreased energy production.

and associated arrhythmias [200].

the most damaged was mitochondrial isoenzyme (activity was suppressed to 17% of normal). This depletion is connected with mitochondrial dysfunction. Effectiveness of mitochondrial oxygen utilization was experimentally evaluated by ADP concentration changes in presence of creatine. During this experiment, the point of ADP concentration where oxygen utilization does not raise independently to increasing APD was noted. And this level was significantly lower in the heart failure group, but at the same time, the oxidative activity of mitochondria was raised up to 30% higher than in the control group. This data shows inhibition of mitochondrial-CK function, also, indirectly, can show that mitochondrial population is decreased, but

CK and mitochondria interactions are very complicated and not only functional

Heart failure is associated with morphological changes in the mitochondria: size reduction, number increase, edema, cristae deformation, homogenization, and IEU damage. The severity of mitochondrial matrix loss is correlated with heart failure stage, and, in addition, mitochondria size variability characterizes respiratory chain

Also, the mitochondria serves as controller of Ca+2 homeostasis in the cytoplasm. The mitochondria regulates Ca-dependent signaling by the means of ion accumulation and energy supplementation for ion pumps, producing an ionic gradient between membranes. The mitochondria directly (SERCA) or indirectly (Na/K pumps) control Ca+2 circulation [16, 119]. Decreased ATP synthesis promotes free Mg+2 accumulation, and its competing effect blocks Ca-dependent Ca release from SR [84]. Then Ca and Na accumulates due to increased activity of Na/H and Na/ Ca+2 pumps, provoking acidosis in cardiomyocytes and decreased buffering ability of the mitochondria [200]. Usually, free Mg+2 concentration is low in the cytoplasm, because it is mostly bounded to ATP, but during ATP loss Mg-ion amounts raise. In this way, we can assume that increased intracellular concentration of free Mg+2 is a

In cases of ATP depletion or oxidative phosphorylation alterations, acidosis is developing. This condition promotes NA accumulation due to activation of Na/H cotransporter. Then inhibition of Na/K pump occurs. While Na accumulates in the cytoplasm, Na/Ca+2 exchange pump activates provoking pathological Ca+2 storage in the cytoplasm, mitochondrial membrane depolarization, and its inability for ionic excess buffering. This condition is predisposing to the accelerated Ca turnover

In general, switching from FFA oxidation to glycolysis during HF characterizes changing of adult heart metabolic pattern to fetal type [97]. This condition leads to disturbances in energy metabolism component gene expression. In experimental models of HF, isogenies, which switched from adult to fetal type, were sequenced [8, 149]. This fetal genotype activation promotes myocardial hypertrophy. One study analyzed 13 metabolism regulating components and expression of the atrial natriuretic peptide (ANP) and heavy beta-myosin chains (beta-MHC) in a normal adult, fetal heart, and in heart failure [139]. The ANP was upregulated in fetal and failing heart, but in HF ANP was not bound to fetal gene overexpression. Stretch, adrenergic hyperactivation, and tachycardia were the reasons for increased ANP in failing heart [147]. Beta-MHC expression was predominant in all three groups in

but also structural. In the cell, the mitochondria forms a crystal-like structure, predisposed to effectively produce energy sources and preserve contractility. Due to the partial isolation of the mitochondria, the contractile function is controlled by small compartments, surrounding each sarcomere and named "Intracellular Energetic Unit" (IEU). One of the most important roles in this system is played by CK isoenzymes (see above). But destructuration of this compartment will lead to substrate supplementation uncoupling and energy starvation [25, 44, 66, 183].

#### *Myocardial Metabolism DOI: http://dx.doi.org/10.5772/intechopen.80870*

*Veterinary Anatomy and Physiology*

decreasing intracellular glucose transport.

insulin resistance is explained by Randle' cycle: high FFA intracellular accumulation promotes raised acetyl-CoA/CoA and NADH/NAD ratios, which inhibits PDH and leads to citrate accumulation and phosphofructokinase inhibition. Associated G6P accumulation inhibits HX2, promoting intracellular glucose accumulation and

Insulin resistance also can be associated with high circulating insulin concentrations. Adrenergic hyperactivity, concomitant to heart failure, leads to increased glucose mobilization, hormone circulation, and insulin synthesis, lipomobilization due to catecholamines (noradrenaline). Insulin stimulates GLUT 4 and CD36 exocytosis, on the first stages it helps to produce enough ATP from glycolysis and oxidative phosphorylation. But insulin receptors have variable action mechanism. Insulin receptors have two places of connection for insulin. One of them has high affinity to hormone and promotes fast response to insulin stimulation; another is a "slow" one and is activated in cases of high insulin concentration and due to geometrical conformation partially blocks the "fast" part of the receptor. In general, insulin resistance is based on the blockade of all "fast" receptors, increased insulin concentration, and fixation of the hormone on "slow" locus of the insulin receptor [9, 11, 13, 14, 94, 116, 152, 175, 190]. Also, a high concentration of circulating FFA decreases insulin-stimulated GLUT 4 translocation. This can be explained by inhibition of Pi 3 kinase of IR-1, which phosphorylation is decreased by TG and phospholipid (FFA-acetyl-CoA, diacylglycerol, ceramides) accumulation in the cytoplasm [26]. GLUT 1 increased expression also takes a part in this process. Increased glucose flux from GLUT 1 promotes decreased GLUT 4 exocytosis and increased GLUT 4 tissue concentration. Developing GLUT 4 function reduction pathological cardiomyocyte hypertrophy and systolic dysfunction occurs [92, 177, 188]. Another factor is pyruvate utilization in anaplerotic reactions, which leads to decreased acetyl-CoA production for Kreb's cycle, glycolysis and oxidative phosphorylation uncoupling, and PDK 4 activation

(promotes inhibition of insulin-stimulated glycolysis) [133].

(pioglitazone, troglitazone) [124, 132].

Also it should be noted that in diabetes and insulin resistance, HX2 activity is decreased. In cell culture experiments, it was found that insulin is HX2 gene expression and protein resynthesis regulator. So, the severity of insulin resistance is a suppressor of HX2 function, leading to G6P accumulation and cytoplasm protein glycosylation. It should be admitted that decreased HX2 microRNA is associated with GLUT 4 genes and protein depletion. These interactions between insulin, HX2, and GLUT can be controlled by insulin sensibilization—by thiazolidinediones

Often heart failure is accompanied by all energy-producing enzyme dysfunction. Significant reduction of activity is noted in creatine kinase (CK) function. This enzyme regulates transfer between ATP and creatine. CK is a dimer and consists of two parts M and B, and there are three isoforms: MM, BB, MB, and mitochondrial-CK [193]. MM-CK is closely connected with SR and coupled with Ca+2-ATPase, producing energy for Ca+2 circulation [182]. Mitochondrial-CK is located on the inner membrane of the mitochondria and works with the ADP-ATP translocator. Produced ATP is transported by translocator to mitochondrial-CK and further to creatine phosphate or ADP. This compartment distribution provides effective control of local ATP/ADP ratio and promotes mitochondrial ATP production (decreased ratio) or increases enzymes activity. But in conditions of cardiomyopathy, the normal compartment system is altered. Decompartmentalization leads to uncoupling of the mitochondria—mitochondrial-CK-ATP and phosphocreatine

One experimental research elucidated CK activity in rats with induced heart failure. General CK activity was decreased to 45% from normal value; in particular,

**70**

interactions [29, 176].

the most damaged was mitochondrial isoenzyme (activity was suppressed to 17% of normal). This depletion is connected with mitochondrial dysfunction. Effectiveness of mitochondrial oxygen utilization was experimentally evaluated by ADP concentration changes in presence of creatine. During this experiment, the point of ADP concentration where oxygen utilization does not raise independently to increasing APD was noted. And this level was significantly lower in the heart failure group, but at the same time, the oxidative activity of mitochondria was raised up to 30% higher than in the control group. This data shows inhibition of mitochondrial-CK function, also, indirectly, can show that mitochondrial population is decreased, but its oxidative function is upregulated [184].

CK and mitochondria interactions are very complicated and not only functional but also structural. In the cell, the mitochondria forms a crystal-like structure, predisposed to effectively produce energy sources and preserve contractility. Due to the partial isolation of the mitochondria, the contractile function is controlled by small compartments, surrounding each sarcomere and named "Intracellular Energetic Unit" (IEU). One of the most important roles in this system is played by CK isoenzymes (see above). But destructuration of this compartment will lead to substrate supplementation uncoupling and energy starvation [25, 44, 66, 183].

Heart failure is associated with morphological changes in the mitochondria: size reduction, number increase, edema, cristae deformation, homogenization, and IEU damage. The severity of mitochondrial matrix loss is correlated with heart failure stage, and, in addition, mitochondria size variability characterizes respiratory chain damage [4, 65].

Also, the mitochondria serves as controller of Ca+2 homeostasis in the cytoplasm. The mitochondria regulates Ca-dependent signaling by the means of ion accumulation and energy supplementation for ion pumps, producing an ionic gradient between membranes. The mitochondria directly (SERCA) or indirectly (Na/K pumps) control Ca+2 circulation [16, 119]. Decreased ATP synthesis promotes free Mg+2 accumulation, and its competing effect blocks Ca-dependent Ca release from SR [84]. Then Ca and Na accumulates due to increased activity of Na/H and Na/ Ca+2 pumps, provoking acidosis in cardiomyocytes and decreased buffering ability of the mitochondria [200]. Usually, free Mg+2 concentration is low in the cytoplasm, because it is mostly bounded to ATP, but during ATP loss Mg-ion amounts raise. In this way, we can assume that increased intracellular concentration of free Mg+2 is a marker of decreased energy production.

In cases of ATP depletion or oxidative phosphorylation alterations, acidosis is developing. This condition promotes NA accumulation due to activation of Na/H cotransporter. Then inhibition of Na/K pump occurs. While Na accumulates in the cytoplasm, Na/Ca+2 exchange pump activates provoking pathological Ca+2 storage in the cytoplasm, mitochondrial membrane depolarization, and its inability for ionic excess buffering. This condition is predisposing to the accelerated Ca turnover and associated arrhythmias [200].

In general, switching from FFA oxidation to glycolysis during HF characterizes changing of adult heart metabolic pattern to fetal type [97]. This condition leads to disturbances in energy metabolism component gene expression. In experimental models of HF, isogenies, which switched from adult to fetal type, were sequenced [8, 149]. This fetal genotype activation promotes myocardial hypertrophy. One study analyzed 13 metabolism regulating components and expression of the atrial natriuretic peptide (ANP) and heavy beta-myosin chains (beta-MHC) in a normal adult, fetal heart, and in heart failure [139]. The ANP was upregulated in fetal and failing heart, but in HF ANP was not bound to fetal gene overexpression. Stretch, adrenergic hyperactivation, and tachycardia were the reasons for increased ANP in failing heart [147]. Beta-MHC expression was predominant in all three groups in

comparison with alpha-MHC. Beta-MHC isogenies were downregulated in fetal and failing hearts, but this is connected with myofilament reduction [51, 73]. Alpha-MHC was reduced by more than 30% in both groups in comparison with the adult heart. These changes are explained by less beta-MHC oxygen and energy demand, but its contractility is also low. In addition, in fetal and failing hearts, FFA oxidation enzymes genes were also suppressed [51, 113, 143].

Fetal genotype is conditioned by hypoxic conditions during embryogenesis, and glycolysis is predominating, while after birth energy metabolism is switched to FFA oxidation. In conditions of pathologic hypertrophy, cardiomyocytes again switched to fetal metabolism in order to survive in the hypoxic environment and energy starvation. In cases of hypertension, this switch appears earlier than in cardiomyopathy [172].

In the adult heart GLUT 4 microRNA expression is rising, while GLUT 1 is decreasing in comparison with fetal heart. In the heart, failure version is observed. The same changes were endured by PDK2, PDK 4, and glycogen synthase. During maturation the amount of mitochondria rises, and, in parallel, citrate synthase gene expression increases. But in failing heart, the mitochondria and citrate synthase are depleted [139].

Adrenergic hyperactivation is associated with high amounts of catecholamines circulating, which promotes reactive oxygen spices (ROS) production. In addition, high amounts of ROS are produced not only by direct stimulation (anthracyclines, tachycardia-induced cardiomyopathy, dilated cardiomyopathy, and etc.) but also by cardiomyocytes overstretch (heart failure with volume overload: valvular diseases, inherited defects) [5, 130, 191].

The main ROS are superoxide (−O2), hydrogen peroxide, and hydroxyl radicals (−OH). Increased formation of this compounds promotes lipid membranes perforation of organelles, DNA, and mitochondria injury [202]. Then this leads to a decrease in SR ATPase, Ca+2 pump, and Na/K pump and Ca+2 accumulation in the cytoplasm [21, 22]. Prolonged exposition to H2O2 provokes CA ion oscillations, leading to Ca-dependent protease activation, mitochondrial membranes perforation, and increasing Ca ion flux through mitochondrial membranes. Combinations of these factors provoke myofilament contracture, damage, and petrification of the mitochondria, and proapoptotic factors release [89].

In veterinary literature, there are studies which elucidate some aspects of the antioxidant system and oxidative stress in dogs with the valvular disease. In these studies, an effect of ROS on valvular structures and on pathogenesis was elucidated, but the certain mechanism is still unknown [134, 142].

As described above there are principal differences between healthy and failing hearts; failing hearts have many similarities with fetal heart metabolic profile. The first stages of metabolic adaptation could differ, while the terminal stage of heart failure has a mostly identical phenotype. Unfortunately, myocardial metabolism in veterinary patients with heart failure is not clearly described. We have lack of proper information and can use some information from human medicine studies (mostly on mice and rats and rarely on dogs, cats, ovine, and embryos). Despite new drugs presented on the veterinary pharmacology market, we can treat heart diseases only on clinical stages and do not have pharmacological tools for prophylaxis. Also, we need to provide specific treatment for some inherited forms of myocardial diseases, such as PDK-dependent dilated cardiomyopathy, and identify the role of taurine and carnitine in arrhythmogenic right ventricle dysplasia/ cardiomyopathy.

**73**

**Author details**

Dmitrii Oleinikov

*Myocardial Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.80870*

provided the original work is properly cited.

Bioprosthesis and Cardioprotection, Russia

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Almazov National Medical Research Center, IEM, Research Laboratory of

\*Address all correspondence to: wolfberg.guard@gmail.com

*Myocardial Metabolism DOI: http://dx.doi.org/10.5772/intechopen.80870*

*Veterinary Anatomy and Physiology*

opathy [172].

depleted [139].

inherited defects) [5, 130, 191].

mitochondria, and proapoptotic factors release [89].

but the certain mechanism is still unknown [134, 142].

enzymes genes were also suppressed [51, 113, 143].

comparison with alpha-MHC. Beta-MHC isogenies were downregulated in fetal and failing hearts, but this is connected with myofilament reduction [51, 73]. Alpha-MHC was reduced by more than 30% in both groups in comparison with the adult heart. These changes are explained by less beta-MHC oxygen and energy demand, but its contractility is also low. In addition, in fetal and failing hearts, FFA oxidation

Fetal genotype is conditioned by hypoxic conditions during embryogenesis, and glycolysis is predominating, while after birth energy metabolism is switched to FFA oxidation. In conditions of pathologic hypertrophy, cardiomyocytes again switched to fetal metabolism in order to survive in the hypoxic environment and energy starvation. In cases of hypertension, this switch appears earlier than in cardiomy-

In the adult heart GLUT 4 microRNA expression is rising, while GLUT 1 is decreasing in comparison with fetal heart. In the heart, failure version is observed. The same changes were endured by PDK2, PDK 4, and glycogen synthase. During maturation the amount of mitochondria rises, and, in parallel, citrate synthase gene expression increases. But in failing heart, the mitochondria and citrate synthase are

Adrenergic hyperactivation is associated with high amounts of catecholamines circulating, which promotes reactive oxygen spices (ROS) production. In addition, high amounts of ROS are produced not only by direct stimulation (anthracyclines, tachycardia-induced cardiomyopathy, dilated cardiomyopathy, and etc.) but also by cardiomyocytes overstretch (heart failure with volume overload: valvular diseases,

The main ROS are superoxide (−O2), hydrogen peroxide, and hydroxyl radicals (−OH). Increased formation of this compounds promotes lipid membranes perforation of organelles, DNA, and mitochondria injury [202]. Then this leads to a decrease in SR ATPase, Ca+2 pump, and Na/K pump and Ca+2 accumulation in the cytoplasm [21, 22]. Prolonged exposition to H2O2 provokes CA ion oscillations, leading to Ca-dependent protease activation, mitochondrial membranes perforation, and increasing Ca ion flux through mitochondrial membranes. Combinations of these factors provoke myofilament contracture, damage, and petrification of the

In veterinary literature, there are studies which elucidate some aspects of the antioxidant system and oxidative stress in dogs with the valvular disease. In these studies, an effect of ROS on valvular structures and on pathogenesis was elucidated,

As described above there are principal differences between healthy and failing hearts; failing hearts have many similarities with fetal heart metabolic profile. The first stages of metabolic adaptation could differ, while the terminal stage of heart failure has a mostly identical phenotype. Unfortunately, myocardial metabolism in veterinary patients with heart failure is not clearly described. We have lack of proper information and can use some information from human medicine studies (mostly on mice and rats and rarely on dogs, cats, ovine, and embryos). Despite new drugs presented on the veterinary pharmacology market, we can treat heart diseases only on clinical stages and do not have pharmacological tools for prophylaxis. Also, we need to provide specific treatment for some inherited forms of myocardial diseases, such as PDK-dependent dilated cardiomyopathy, and identify the role of taurine and carnitine in arrhythmogenic right ventricle dysplasia/

**72**

cardiomyopathy.
