**3. Regulation of carbohydrates and FFA oxidation**

The main regulator of carbohydrates oxidation is FFA utilization. Increased FFA consumption leads to its intermediate accumulation, which blocks PDH. At the same time, decreased FFA consumption promotes glycolysis and lactate oxidation, due to citrate, NADH, and acetyl-CoA deficiency in the mitochondrial matrix. The last part is often noted in cardiomyopathies and during ischemia [54, 161].

Modern researches showed an impressive role of small molecule proteins energy homeostasis regulators. Of course, there are many molecules and factors that control energy metabolism, one stimulates appetite (ghrelin, galanin, neuropeptide Y) and another is an anorexigenic (leptin, nesfatin-1) [71, 155]. The first found molecule, which regulates energetic homeostasis, was insulin (Ins); its action was first noted as neurogenic appetite suppression. Later leptin was found—hormone, produced by adipose tissue—and elucidates general adipose tissue state [199]. Then ghrelin and nesfatin-1 were found, with antagonist action to leptin effects on adipose tissue [77, 120]. On the next decades, there was intensive research in the field of lipid homeostasis and appetite-controlling peptides. Many molecules were found; the most important are preptin, irisin, and adropin.

Insulin (Ins) is a hormone with a huge specter of physiological influence, but in this papers, we discuss only three effects: on heart pump function, on Ca+2 ion circulation, and as a mediator between cell communication. Ins-induced transport of glucose is the main mechanism of energy production of membrane-associated ATPases and ion pumps. Controlling pump function, Ins indirectly influences cytoplasmic concentration and equilibration of Ca+2; it mediates cascades of reactions to stimulate Ca consumption or excretion. Ins is involved in endothelial function, regulating NO production and tissue perfusion (including coronary vessels). And, of course, it influences on the contractile ability of cardiomyocytes due to energy metabolism modulation.

As an indirect effect, abilities of Ins to control the availability of energy substrates (effects on liver and adipose tissue) and tissue perfusion should be noted. Ins inhibits TG hydrolysis in adipose tissue (depressing lipomobilizating hormones), decreasing the level of circulating FFA. In addition, reactive Ins secretion increases tissue perfusion due to blood vessels smooth muscle relaxation. This effect plays a significant role during exercise, hypertension, and acute and chronic heart failure [70, 136, 165].

Direct Ins action regulates key enzymes (6-phosphofructokinase 1 and 2, glycogen phosphorylase and synthase, PDH, hormone-dependent lipase, acetyl-CoA carboxylase) and transporters (GLUT family, CPT-1, CD36/FAPT). Interactions between main metabolic substrates (glucose and FFA) are elucidated by Randle's cycle [136]. Transmembrane glucose transport by GLUT 1 and GLUT 4 is modulated by Ins (both transporters are Ins-determined, but GLUT 1 is less dependent). GLUT 4 is significantly presented in myocardium tissue; this helps to sustain myocardial energy flexibility in exercises and heart failure. Ins influence on glycogen accumulation in several ways: decreasing glucose utilization (FFA oxidation predominance, leads to PDH blockade, glucose intermediates converted to glycogen); HX2 converting capacity in overloaded glucose transport (Ins-dependent GLUT 4 exocytosis); glycogen utilization in glucose depletion. It should be mentioned that glycogen is oxidized more actively, than glucose, due to its already intracellular location and production of more ATP. In addition, Ins stimulates glycogen synthase directly and through G6P raise [52, 86]. Ins and PDH interactions are not clear. We should consider the effects of FFA oxidation suppression (decreased acetyl-CoA concentration in mitochondria), influence on PDH phosphatase, NAD/NADH ratio, and Ca+2 concentration. Generally, Ins is controlling glycolysis indirectly by metabolite and substrate availability and directly through enzymatic systems (mentioned above). Ins' influence on FFA oxidation is closely connected with its effects on glycolysis and partly described above. By the way, Ins suppresses CPT-1 function, due to malonyl-CoA concentration. It can be explained by the fact that malonyl-CoA is produced by acetyl-CoA carboxylase, which is in direct control of Ins [57, 58].

Mediator effect of Ins between cells is described by its effects on PDH, HX2, phosphofructokinase, glycogen synthase, acetyl-CoA carboxylase, hormonedependent lipase, PDH kinase, MAP kinase, and lactate intercellular shuttle and based on metabolic influence.

As for leptin, its effects were observed in recent research of dogs with chronic degenerative valve disease. In the experiment the raise of circulating leptin and leptin microRNA in this disease was noted. Observed dogs were not suffering from obesity, so found leptin changes are connected with heart failure syndrome. In addition, the correlation between leptin level and heart failure severity was found [45].

Preptin is a hormone modulating carbohydrate metabolism; it is a part of the insulin family (as insulin, insulin-like growth factor-1, proinsulin-like factor-2, relaxin-2). In experiments, it was found that it is secreted together with insulin and promotes glucose utilization in insulin-like ways. There was a strong connection between preptin expression and insulin resistance. Generally, this hormone plays a role in hepatic glycogenesis and bone density (osteoclasts proliferation) and modulates sensitivity to insulin and adaptation to energetic substrates [1, 10, 126, 186].

Adropin is a recently found hormone controlling lipid metabolism. Adropin regulates energy metabolism, depending on the diet type (significantly raised on a high-fat diet). Systemic administration of adropin decreases hepatosteatosis and hyperinsulinemia severity (moderating carbohydrate-FFA metabolism in peripheral tissues). In researches, a connection between heart failure severity and circulating adropin concentration (high severity of heart failure-high adropin level) was noted. Also in insulin resistance, the level of circulating adropin is decreased and correlated with atherosclerosis risks in diabetes mellitus. Low levels of adropin were associated with endothelial dysfunction and high risk of heart X syndrome. Adropin suppresses the activity of PDH kinase 4, which promotes normal pyruvate utilization in Krebs cycle and decreases CPT-1 activity and traffic of CD36 transporters, decreasing FFA transport in cardiomyocytes. The main functions of adropin consist of regulating NO availability, decreasing lipogenic gene expression,

**67**

activation [35, 48].

acidosis, Ca+2 hyperaccumulation [192].

*Myocardial Metabolism*

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

phagocytes, lymphocytes, etc.) [159].

decreasing dyslipidemia and hepatic steatosis, modifying insulin resistance and glucose tolerance, and controlling metabolic homeostasis [37–39, 82, 91, 168].

ance, decreasing obesity, and modulating insulin resistance [144, 198].

damage and cardiomyocyte apoptosis [2, 43, 105, 123, 148].

genes and decreasing cAMP in cardiomyocytes [41, 42, 74, 179].

Besides, there are also biologically active molecules, which have paracrine effects. This molecule does not affect myocardial metabolism by itself, but promoting reactions could affect the contractile ability of cardiomyocytes. Among them are cytokines, thrombocyte-activating factor (TAF), reactive oxygen species (ROS), arachidonic acid, and nitrogen oxide (NO). The sources of these peptides are the cardiomyocyte itself, endotheliocytes, and migrating immune cells (mononuclear

Cytokines include TNF-a, IL-1, and IL-6. TNF-a is produced in cardiomyocytes during injury; the most effects of this peptide are described in ischemia–reperfusion syndrome, due to its significant negative inotropic effect. The main promoters of TNF-a production are hypoxia and ROS. Negative inotropic effect development is staged. First, immediately after the injury, sphingosine is produced from sphingomyelin, which inhibits RyR2 receptors of SR and decreases Ca+2-dependent Ca+2 release, suppressing contractility. In parallel, direct cytotoxic effect developed, due to mitochondrial oxidation uncoupling. And then, NO-dependent Ca+2 transport suppression is developed. Produced NO-superoxide promotes contractile filament

Interleukins are the main inflammatory mediators; their action closely interacted with TNF-a, developing NO release, suppression of Ca+2 turn over regulation

Thrombocyte-activating factor (TAF) is a phosphoglyceride with a potent pro-inflammatory effect. This cytokine is produced by cardiomyocytes, endotheliocytes, and histiocytes. TAF pathological effects are associated with significant vasoconstriction, contractility decrease, ROS, and superoxide release and autolysis

Arachidonic acid and its metabolites is part of membrane phospholipids in cardiomyocytes, but in case of injury, these compounds are degraded by phospholipase A2, which is high Ca+2 concentration-dependent. Arachidonic metabolites damage ionic channels components, receptors, intercalated disks and provoke cytoplasmic

Adenosine is a metabolite of adenine nucleotide; it has a wide specter of action: coronary artery dilatation, negative chronotropic, dromotropic, and inotropic effects by means of A1 and A2 receptors. Adenosine is also a catecholamine antagonist (decreases cAMP activity), stimulates protein kinase C (PKC), promotes macroergic compounds restoration, and inhibits some ROS and neutrophils activity [88, 157]. PKC is a part of intracellular myocardial metabolism regulation. This kinase is sensitive to Ca+2 cytoplasm accumulation, angiotensin II, phenylephrine, and endothelin stimulation. As a response to this stimulation, PKC downregulates troponin; sensitivity of troponin to Ca+2 promotes myofibrillar disruption and decreases

Irisin is a hormone controlling the conversion of white to brown adipose tissue. The white adipose tissue has a lack of mitochondria and lots of TG and FFA and produces leptin, ghrelin, nesfatin-1 [15, 27, 135, 178]. While the brown adipose tissue contains lots of mitochondria and lipid droplets. In this cell, high amounts of uncoupling protein-1 are presented. This protein promotes uncoupling of ATP production from FFA oxidation, instead of ADP phosphorylation, and produces heat [62]. In experiments, it was noted that high amounts of circulating irisin are presented in cases of obesity, which can be characterized as irisin resistance (insulin resistance-like) [166]. Irisin is predominantly synthesized in skeletal muscles during exercises. The main actions of this hormone are toward decreasing of white adipose tissue, controlling temperature homeostasis, increasing of glucose toler-

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

*Veterinary Anatomy and Physiology*

Direct Ins action regulates key enzymes (6-phosphofructokinase 1 and 2, glycogen phosphorylase and synthase, PDH, hormone-dependent lipase, acetyl-CoA carboxylase) and transporters (GLUT family, CPT-1, CD36/FAPT). Interactions between main metabolic substrates (glucose and FFA) are elucidated by Randle's cycle [136]. Transmembrane glucose transport by GLUT 1 and GLUT 4 is modulated by Ins (both transporters are Ins-determined, but GLUT 1 is less dependent). GLUT 4 is significantly presented in myocardium tissue; this helps to sustain myocardial energy flexibility in exercises and heart failure. Ins influence on glycogen accumulation in several ways: decreasing glucose utilization (FFA oxidation predominance, leads to PDH blockade, glucose intermediates converted to glycogen); HX2 converting capacity in overloaded glucose transport (Ins-dependent GLUT 4 exocytosis); glycogen utilization in glucose depletion. It should be mentioned that glycogen is oxidized more actively, than glucose, due to its already intracellular location and production of more ATP. In addition, Ins stimulates glycogen synthase directly and through G6P raise [52, 86]. Ins and PDH interactions are not clear. We should consider the effects of FFA oxidation suppression (decreased acetyl-CoA concentration in mitochondria), influence on PDH phosphatase, NAD/NADH ratio, and Ca+2 concentration. Generally, Ins is controlling glycolysis indirectly by metabolite and substrate availability and directly through enzymatic systems (mentioned above). Ins' influence on FFA oxidation is closely connected with its effects on glycolysis and partly described above. By the way, Ins suppresses CPT-1 function, due to malonyl-CoA concentration. It can be explained by the fact that malonyl-CoA is produced by acetyl-CoA carboxylase, which is in direct control of

Mediator effect of Ins between cells is described by its effects on PDH, HX2, phosphofructokinase, glycogen synthase, acetyl-CoA carboxylase, hormonedependent lipase, PDH kinase, MAP kinase, and lactate intercellular shuttle and

As for leptin, its effects were observed in recent research of dogs with chronic degenerative valve disease. In the experiment the raise of circulating leptin and leptin microRNA in this disease was noted. Observed dogs were not suffering from obesity, so found leptin changes are connected with heart failure syndrome. In addition, the correlation between leptin level and heart failure severity was found [45]. Preptin is a hormone modulating carbohydrate metabolism; it is a part of the insulin family (as insulin, insulin-like growth factor-1, proinsulin-like factor-2, relaxin-2). In experiments, it was found that it is secreted together with insulin and promotes glucose utilization in insulin-like ways. There was a strong connection between preptin expression and insulin resistance. Generally, this hormone plays a role in hepatic glycogenesis and bone density (osteoclasts proliferation) and modulates sensitivity to insulin and adaptation to energetic substrates [1, 10, 126, 186]. Adropin is a recently found hormone controlling lipid metabolism. Adropin regulates energy metabolism, depending on the diet type (significantly raised on a high-fat diet). Systemic administration of adropin decreases hepatosteatosis and hyperinsulinemia severity (moderating carbohydrate-FFA metabolism in peripheral tissues). In researches, a connection between heart failure severity and circulating adropin concentration (high severity of heart failure-high adropin level) was noted. Also in insulin resistance, the level of circulating adropin is decreased and correlated with atherosclerosis risks in diabetes mellitus. Low levels of adropin were associated with endothelial dysfunction and high risk of heart X syndrome. Adropin suppresses the activity of PDH kinase 4, which promotes normal pyruvate utilization in Krebs cycle and decreases CPT-1 activity and traffic of CD36 transporters, decreasing FFA transport in cardiomyocytes. The main functions of adropin consist of regulating NO availability, decreasing lipogenic gene expression,

**66**

Ins [57, 58].

based on metabolic influence.

decreasing dyslipidemia and hepatic steatosis, modifying insulin resistance and glucose tolerance, and controlling metabolic homeostasis [37–39, 82, 91, 168].

Irisin is a hormone controlling the conversion of white to brown adipose tissue. The white adipose tissue has a lack of mitochondria and lots of TG and FFA and produces leptin, ghrelin, nesfatin-1 [15, 27, 135, 178]. While the brown adipose tissue contains lots of mitochondria and lipid droplets. In this cell, high amounts of uncoupling protein-1 are presented. This protein promotes uncoupling of ATP production from FFA oxidation, instead of ADP phosphorylation, and produces heat [62]. In experiments, it was noted that high amounts of circulating irisin are presented in cases of obesity, which can be characterized as irisin resistance (insulin resistance-like) [166]. Irisin is predominantly synthesized in skeletal muscles during exercises. The main actions of this hormone are toward decreasing of white adipose tissue, controlling temperature homeostasis, increasing of glucose tolerance, decreasing obesity, and modulating insulin resistance [144, 198].

Besides, there are also biologically active molecules, which have paracrine effects. This molecule does not affect myocardial metabolism by itself, but promoting reactions could affect the contractile ability of cardiomyocytes. Among them are cytokines, thrombocyte-activating factor (TAF), reactive oxygen species (ROS), arachidonic acid, and nitrogen oxide (NO). The sources of these peptides are the cardiomyocyte itself, endotheliocytes, and migrating immune cells (mononuclear phagocytes, lymphocytes, etc.) [159].

Cytokines include TNF-a, IL-1, and IL-6. TNF-a is produced in cardiomyocytes during injury; the most effects of this peptide are described in ischemia–reperfusion syndrome, due to its significant negative inotropic effect. The main promoters of TNF-a production are hypoxia and ROS. Negative inotropic effect development is staged. First, immediately after the injury, sphingosine is produced from sphingomyelin, which inhibits RyR2 receptors of SR and decreases Ca+2-dependent Ca+2 release, suppressing contractility. In parallel, direct cytotoxic effect developed, due to mitochondrial oxidation uncoupling. And then, NO-dependent Ca+2 transport suppression is developed. Produced NO-superoxide promotes contractile filament damage and cardiomyocyte apoptosis [2, 43, 105, 123, 148].

Interleukins are the main inflammatory mediators; their action closely interacted with TNF-a, developing NO release, suppression of Ca+2 turn over regulation genes and decreasing cAMP in cardiomyocytes [41, 42, 74, 179].

Thrombocyte-activating factor (TAF) is a phosphoglyceride with a potent pro-inflammatory effect. This cytokine is produced by cardiomyocytes, endotheliocytes, and histiocytes. TAF pathological effects are associated with significant vasoconstriction, contractility decrease, ROS, and superoxide release and autolysis activation [35, 48].

Arachidonic acid and its metabolites is part of membrane phospholipids in cardiomyocytes, but in case of injury, these compounds are degraded by phospholipase A2, which is high Ca+2 concentration-dependent. Arachidonic metabolites damage ionic channels components, receptors, intercalated disks and provoke cytoplasmic acidosis, Ca+2 hyperaccumulation [192].

Adenosine is a metabolite of adenine nucleotide; it has a wide specter of action: coronary artery dilatation, negative chronotropic, dromotropic, and inotropic effects by means of A1 and A2 receptors. Adenosine is also a catecholamine antagonist (decreases cAMP activity), stimulates protein kinase C (PKC), promotes macroergic compounds restoration, and inhibits some ROS and neutrophils activity [88, 157].

PKC is a part of intracellular myocardial metabolism regulation. This kinase is sensitive to Ca+2 cytoplasm accumulation, angiotensin II, phenylephrine, and endothelin stimulation. As a response to this stimulation, PKC downregulates troponin; sensitivity of troponin to Ca+2 promotes myofibrillar disruption and decreases

contractile ability, fibrosis, and hypertrophy of cardiomyocytes. In experiments, it was noted that increased PKC expression provokes myocardial hypertrophy and fetal metabolic genotype activation and significantly alters Ca+2 ion transmembrane circulation [7, 185, 187]. This can be explained by decreased SERCA2 and phospholamban protein expression, suppression of Na/CA and Na/H ionic pumps, PKC-dependent phosphorylation of the myofilament and troponin proteins, and downregulation of Ca+2-dependent membrane transporters, which indirectly negatively influence on energy metabolism [174].

CaMKK II—calmodulin-dependent kinase— is activated by Ca+2 accumulation in the cytoplasm. CaMKK II independently or by AMPK stimulation promotes GLUT 4 trafficking and exocytosis. In experiments a compound stimulation of GLUT 4 exocytosis and its retention on the outer part of the cell membrane by AMP, PKC, and CaMKK II was elucidated. By these means, muscle contraction promotes GLUT 4 exocytosis and glucose transport, but in cases of pathologic Ca+2 cytoplasm accumulation, GLUT 4 could not move into the cell, which alters glucose consumption and promotes increasing of FFA utilization (Randle cycle). Catecholamine-induced tachycardia provokes altered GLUT 4 endocytosis, insulin resistance, and glycolysis inhibition [90].

As already been said, there are many regulating mediators. However, Ca+2 ions can influence myocardial metabolism by themselves. The raise of Ca cytoplasmic concentration (SR release) is determined by the following mechanisms: Ca+2-dependent Ca+2 release (calcium sparks), SR depolarization, pH changes, voltage-dependent changes of T-tubules and triad membranes, and inositol-dependent release. Calcium provokes GLUT 4 exocytosis and increases glucose consumption. First, this effect was described in experiments with caffeine influence on cardiomyocytes. Myocytes began to utilize glucose, while being incubated with low caffeine concentration.

Nitric oxide decreases cardiomyocyte utilization of glucose due to cGMP effects. In experiments, it was noted that NO-synthase blockade promotes stabilization of ischemic myocardium metabolic state. Some researchers pointed at fact that cGMP and glucose metabolism are not connected, so the real influence of No on metabolism is not clear, but its effects should be noted. In addition, NO has a negative inotropic effect in inhibiting Ca-channel and producing superoxide (peroxynitrite) [17–19, 83, 170, 197].

### **4. Energy substrates and contractility**

Muscle contraction is a multifactor process, including energy status changes (ATP/AMP ratio variation), increased intercellular Ca+2 accumulation, stretch, GLUT 4 exocytosis, glucose and FFA consumption, etc.

Many types of research showed the high effectiveness of myocardial contractility in conditions of intensive glucose utilization, and, at the same time, increased FFA consumption on 26% did not promote equal raise in contractility, but only oxygen demand raised [109, 154]. Target disabling FFA oxidation reactions and FFA bounding to not available compounds decreases oxygen demand and increases the mechanic power of rat's heart contraction. Combination of insulin and glucose promotes to decrease the heart's oxygen demand to 39% [79]. These effects are not clearly understood because theoretically palmitate or oleate utilization need fewer molecules of O2 to produce one molecule of ATP in comparison with glucose or lactate. A possible explanation is connected with interactions between long-chained FFA and Ca+2 channels (increases ATP demand for a pump ATP-ase) [75, 109, 154].

Recent studies showed that increased concentration of FFA and TG in the cytoplasm can provoke lipotoxicity in the myocardium, presented in neutral lipids and

**69**

*Myocardial Metabolism*

151, 156, 158, 180, 194, 195].

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

ceramides accumulation, leading to cell's apoptosis and decreased contractility. In experiments, Zhou showed that in the diabetic rat, high rates of TG and ceramides were accumulated, promoting DCM-phenotype changes, decreased contractility, and high indexes of cardiomyocytes apoptosis. Nevertheless, in the case of troglitazone, the manifestation of the FFA block mentioned significantly decreased. By this time lipid-induced myocardium remodeling is still mostly unknown, but this process could be associated with cell apoptosis, decreased contractility due to intensive FFA utilization and significantly depressed glycolysis [53, 108, 125, 150,

Heart failure syndrome, despite etiology, development is always associated with an energy deficit. During this state individual cardiomyocytes are under the increased workload associated with the high demand for macroergic substrates, but their production is severely depleted. This state is so-called an engine out of fuel due to decreased amounts of creatine phosphate and ATP [115]. Compensatory and pathological cardiomyocyte hypertrophy is associated with decreased creatine phosphate/ATP ratio, and later ATP decreases too. The creatine phosphate/ATP ratio

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

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 poten-

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

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

is a reliable prognostic marker in heart failure worsening [114].

**5. Myocardial metabolism in heart failure**

amounts of ATP, then FFA oxidation [3, 79].

changes observed in the left heart failure [129].

tial ГЛЮТ1 [87, 110].

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

*Veterinary Anatomy and Physiology*

negatively influence on energy metabolism [174].

resistance, and glycolysis inhibition [90].

**4. Energy substrates and contractility**

GLUT 4 exocytosis, glucose and FFA consumption, etc.

[17–19, 83, 170, 197].

contractile ability, fibrosis, and hypertrophy of cardiomyocytes. In experiments, it was noted that increased PKC expression provokes myocardial hypertrophy and fetal metabolic genotype activation and significantly alters Ca+2 ion transmembrane circulation [7, 185, 187]. This can be explained by decreased SERCA2 and phospholamban protein expression, suppression of Na/CA and Na/H ionic pumps, PKC-dependent phosphorylation of the myofilament and troponin proteins, and downregulation of Ca+2-dependent membrane transporters, which indirectly

CaMKK II—calmodulin-dependent kinase— is activated by Ca+2 accumulation

As already been said, there are many regulating mediators. However, Ca+2 ions can

Nitric oxide decreases cardiomyocyte utilization of glucose due to cGMP effects. In experiments, it was noted that NO-synthase blockade promotes stabilization of ischemic myocardium metabolic state. Some researchers pointed at fact that cGMP and glucose metabolism are not connected, so the real influence of No on metabolism is not clear, but its effects should be noted. In addition, NO has a negative inotropic effect in inhibiting Ca-channel and producing superoxide (peroxynitrite)

Muscle contraction is a multifactor process, including energy status changes (ATP/AMP ratio variation), increased intercellular Ca+2 accumulation, stretch,

Many types of research showed the high effectiveness of myocardial contractility in conditions of intensive glucose utilization, and, at the same time, increased FFA consumption on 26% did not promote equal raise in contractility, but only oxygen demand raised [109, 154]. Target disabling FFA oxidation reactions and FFA bounding to not available compounds decreases oxygen demand and increases the mechanic power of rat's heart contraction. Combination of insulin and glucose promotes to decrease the heart's oxygen demand to 39% [79]. These effects are not clearly understood because theoretically palmitate or oleate utilization need fewer molecules of O2 to produce one molecule of ATP in comparison with glucose or lactate. A possible explanation is connected with interactions between long-chained FFA and Ca+2 channels (increases ATP demand for a pump ATP-ase) [75, 109, 154]. Recent studies showed that increased concentration of FFA and TG in the cytoplasm can provoke lipotoxicity in the myocardium, presented in neutral lipids and

influence myocardial metabolism by themselves. The raise of Ca cytoplasmic concentration (SR release) is determined by the following mechanisms: Ca+2-dependent Ca+2 release (calcium sparks), SR depolarization, pH changes, voltage-dependent changes of T-tubules and triad membranes, and inositol-dependent release. Calcium provokes GLUT 4 exocytosis and increases glucose consumption. First, this effect was described in experiments with caffeine influence on cardiomyocytes. Myocytes began

to utilize glucose, while being incubated with low caffeine concentration.

in the cytoplasm. CaMKK II independently or by AMPK stimulation promotes GLUT 4 trafficking and exocytosis. In experiments a compound stimulation of GLUT 4 exocytosis and its retention on the outer part of the cell membrane by AMP, PKC, and CaMKK II was elucidated. By these means, muscle contraction promotes GLUT 4 exocytosis and glucose transport, but in cases of pathologic Ca+2 cytoplasm accumulation, GLUT 4 could not move into the cell, which alters glucose consumption and promotes increasing of FFA utilization (Randle cycle). Catecholamine-induced tachycardia provokes altered GLUT 4 endocytosis, insulin

**68**

ceramides accumulation, leading to cell's apoptosis and decreased contractility. In experiments, Zhou showed that in the diabetic rat, high rates of TG and ceramides were accumulated, promoting DCM-phenotype changes, decreased contractility, and high indexes of cardiomyocytes apoptosis. Nevertheless, in the case of troglitazone, the manifestation of the FFA block mentioned significantly decreased. By this time lipid-induced myocardium remodeling is still mostly unknown, but this process could be associated with cell apoptosis, decreased contractility due to intensive FFA utilization and significantly depressed glycolysis [53, 108, 125, 150, 151, 156, 158, 180, 194, 195].

Heart failure syndrome, despite etiology, development is always associated with an energy deficit. During this state individual cardiomyocytes are under the increased workload associated with the high demand for macroergic substrates, but their production is severely depleted. This state is so-called an engine out of fuel due to decreased amounts of creatine phosphate and ATP [115]. Compensatory and pathological cardiomyocyte hypertrophy is associated with decreased creatine phosphate/ATP ratio, and later ATP decreases too. The creatine phosphate/ATP ratio is a reliable prognostic marker in heart failure worsening [114].
