**5. Pathomorphological measurements of myocardium in TGA infants**

Data on morphological measurements of myocardium samples of TGA infants and infants of the same age but with intact myocardium are given in Table 9. As is seen from Table 9, the myocardium mass increased by 2.0 – 2.5 times and it tended to increase over age, i.e. in TGA infants the increase in the heart's mass considerably exceeded the normal age-related values for the heart's mass. Morphometric measurement data show that, in comparison with the intact myocardium, the TGA infants' myocardium had a reduced diameter of muscle fibres and a reduced mean area of nucleus and lowered nucleus-cytoplasma ratios in RV. However, the volumetric density and relative area of muscle tissue surface tended to increase.


Table 9. Morphometric parameters of TGA infants' myocardium

the activity of b-DNA-polymerase directly depends on the content of Cr, a vital chemical element (Panchenko, 2004). Cr deficiency is observed in premature infants, whose mothers do not get enough of it in their diet. Chlorous channels can be found in mitochondrial membranes and muscle tissue. Also, chloride ions regulate the liquid volume and stabilize pH of the cells (Sing & Snow, 1998). Rb is an analogue of K and together with Cl they are very active in redoxreactions. A considerable deficiency of Se, which protects cardiomyocytes from detrimental effects of free radicals, has the greatest impact on cardiomyocyte metabolism. A decrease in muscle mass and a developmental lag were observed in newborns whose mothers were short of Se during pregnancy (Panchenko et al., 2004). In the case of Se deficiency, the cells start dying both in the form of apoptosis and necrosis, which might result in the sudden death of newborns (Azoicai et al., 1997; Bolli, 2002). On the strength of these data, we suggest that a very low content of CE, and Se in particular, in the myocardium could lead to structural disorders in the development of heart

**5. Pathomorphological measurements of myocardium in TGA infants** 

Data on morphological measurements of myocardium samples of TGA infants and infants of the same age but with intact myocardium are given in Table 9. As is seen from Table 9, the myocardium mass increased by 2.0 – 2.5 times and it tended to increase over age, i.e. in TGA infants the increase in the heart's mass considerably exceeded the normal age-related values for the heart's mass. Morphometric measurement data show that, in comparison with the intact myocardium, the TGA infants' myocardium had a reduced diameter of muscle fibres and a reduced mean area of nucleus and lowered nucleus-cytoplasma ratios in RV. However, the volumetric density and relative area of muscle tissue surface tended to

parameters Heart part Infants TGA infants

LV 14.6±0.79 12.0±1.47 RV 13.1±1.13 11.4±1.35

LV 265±22.8 287±27.3

RV 274±27.3 286±37.6

LV 0.78±0.067 0.85±0.08 RV 0.81±0.081 0.84±0.11

LV 41±2.5 45±7.1 RV 53±1.5 34±7.7

LV 2358±211.8 2073±107.1 RV 2534±289.1 2063±355.8

LV 0.37 0.33 RV 0.49 0.26

parts and, consequently, to deaths among TGA infants.

increase.

Morphometric

Muscle tissue diameter, µm

Relative area of muscle tissue surface, µm²

Volumetric density of muscle tissue

Number of nuclei per field of vision

> Mean area of nucleus, µm²

Nucleuscytoplasmic ratio

Table 9. Morphometric parameters of TGA infants' myocardium

Depending on the anatomic type, 2 groups of TGA patients prevail: the first group, the socalled simple TGA form, TGA with atrial septal defect (ASD) and intact ventricular septum (IVS), and the second group, which includes TGA patients with ASD and VSD.

From the point of view of hemodynamics, the first group of TGA patients with IVS features a two-directional shunt, the volume of which, when performing isolated shunting on the level of atria, will depend on compliance of atria, a pressure differential in them during different phases of the cardiac cycle, size of atrial defect and a difference in resistance of the systemic and pulmonary circulation. Since the systemic circulation and pulmonary circulation are separated, the main compensation strategy is to increase the volume of circulating blood, which leads to overflow of the pulmonary circulation system (Adkin et al., 2002). In this anatomic type of TGA, the functional load on the ventricles is practically the same, which is confirmed by the results obtained while staining the myocardium with ethidium bromide. These results indicate that the peak of active synthesis of genetic material uptake in both ventricles in this group, as compared to that in the control group (see Fig. 2A), occurs during the neonatal period and manifests itself as a dramatic drop in colour intensity in fluorescence (see Fig. 2B).

The second group of TGA patients with VSD is hemodynamically characterized by the presence of 2 defects, on the level of atrial and ventricular septa, which improves blood mixing on the ventricular level due to crossed shunting. With VSD size being small, the pressure in pulmonary circulation grows slightly, when the size of VSD is large, the pressure in both circulation systems is levelled out which results in high pulmonary hypertension (HPHT) and augmentation of hypoxemia (Bokeria, 1996; Isoyama et al., 1987). In this anatomic type of TGA, due to an increase in the blood volume, both ventricles are subject to a large functional load as compared with the first group of patients, which makes itself evident in a reduced level of fluorescence in infancy (1 to 6 months old). From our point of view, this phenomenon can be defined as the start of the heart remodelling processes, which at the age of older than 6 months also include hyperplastic processes. These processes are related to polyploidization of nuclear material and subsequent hypertrophic phenomena determined by appropriate hemodynamic conditions developed during the postnatal period.

Fig. 2A. Control group (up to 1 month). LV myocardium. Magnification 260. Filter set 14. BP510-560nm. FT580. LP 590nm. Staining with ethidium bromide.

Chemical Elements and Structural/Molecular

oxygen saturation down to 32 %.

number of myofibrils, which aggravates cardiac insufficiency.

Properties of Myocardium in Infants with Transposition of Great Arteries 343

IVS. Measuring the content of CE in groups with IVS and VSD resulted in the following findings. The content of Cu, Zn and Mn in the group with VSD is 1.3 – 1.5 times higher than in the group with IVS. The content of CE in LV and RV of patients with IVS was about the same, except for an increased content of Mn in LV. At the same time, the content of CE in RV of patients with VSD increased, compared with that in LV, notably higher were concentrations of Zn, Mn and, to a lesser extent, Cu, Cr, Br, Rb. These findings are also confirmed by the cardiometric data (see the Table). In the case of the type with IVS, hypertrophic processes in LV and RV develop uniformly, and CE concentrations in LV and RV do not differ essentially. In the second type of TGA with VSD, the right ventricle has to bear a large functional load, therefore, CE concentration in RV is higher than in LV. It agrees with more pronounced structural changes in coronary arteries in the functionally overloaded RV in patients with VSD. However, despite intensive cardiac work in the cases of ASD and VSD, oxygen delivery in this group of patients is worse because of lower blood

The reduction of the numeric content of total ions Ca2+ is caused by the development of hypertrophic phenomena in the myocardium of patients with congenital heart diseases (see Fig. 3A and 3B). Most probably, these hypertrophic phenomena result from a decrease in the

Fig. 3A. Control group. Native sample of LV wall. A high level of fluorescence. Filter set 05.

BP395-440nm. FT460. LP 470nm. Magnification 260. Staining with chlortetracycline.

Fig. 2B. TGA with IVS. Lowered fluorescence level. LV myocardium (1 to 6 months). Magnification 260. Filter set 14. BP510-560nm. FT580. LP 590nm. Staining with ethidium bromide.

Clinical examination of TGA patients classified as belonging to the first anatomic type, i.e. with IVS, revealed an increase with age in cardiac insufficiency, respiration rate, liver dimensions, as well as a reduction in blood oxygen saturation on average, down to 60.9+13.5%. Arterial pressure and cardiac rate were within the normal age limits.

All TGA patients from the VSD group had pronounced cardiac insufficiency, increased respiration rate and liver dimensions, and decreased blood oxygen saturation, down to 32. 5+12.5% (р<0.05 ). Arterial pressure and cardiac rate were within the normal age limits. According to echocardiographic data, TGA patients from both groups, as compared with newborns, tended to show with age an increase in the following indicators: RV size (endsystolic dimension, stroke output, end-diastolic volume) and LV thickness. These changes imply a tendency towards a decrease in the contractile potential of the myocardium. The senior group of patients with VSD demonstrated a higher pressure in the pulmonary artery, up to 76.5+2.1 mm Hg.

LV muscle mass was growing faster by 6 to 12 months in the patients with VSD, with this value remaining stable in the IVS group. The mean quantity of nuclei was initially lower than in the control group, while the average area of nuclei was, to the contrary, higher but tended to decrease with age as well. The total area of nuclei in the control group tended to decrease. In the first group with IVS, this process took place faster, while in the second group there was an increase of this value, which is indicative of a compensatory reaction of LV. With age the surface density of cardiomyocytes smoothly grew in all the groups. The nucleus-cytoplasmic ratio in LV gradually decreased with age in infants of all groups. More pronounced was this tendency in RV of TGA patients with IVS. Conversely, a slight increase in this ratio was noted in TGA patients with VSD.

Studying the number density of capillaries revealed their simultaneous changes in both groups, with the highest point occurring at the age of 1 month in LV and RV in patients with

Fig. 2B. TGA with IVS. Lowered fluorescence level. LV myocardium (1 to 6 months). Magnification 260. Filter set 14. BP510-560nm. FT580. LP 590nm. Staining with ethidium

60.9+13.5%. Arterial pressure and cardiac rate were within the normal age limits.

Clinical examination of TGA patients classified as belonging to the first anatomic type, i.e. with IVS, revealed an increase with age in cardiac insufficiency, respiration rate, liver dimensions, as well as a reduction in blood oxygen saturation on average, down to

All TGA patients from the VSD group had pronounced cardiac insufficiency, increased respiration rate and liver dimensions, and decreased blood oxygen saturation, down to 32. 5+12.5% (р<0.05 ). Arterial pressure and cardiac rate were within the normal age limits. According to echocardiographic data, TGA patients from both groups, as compared with newborns, tended to show with age an increase in the following indicators: RV size (endsystolic dimension, stroke output, end-diastolic volume) and LV thickness. These changes imply a tendency towards a decrease in the contractile potential of the myocardium. The senior group of patients with VSD demonstrated a higher pressure in the pulmonary artery,

LV muscle mass was growing faster by 6 to 12 months in the patients with VSD, with this value remaining stable in the IVS group. The mean quantity of nuclei was initially lower than in the control group, while the average area of nuclei was, to the contrary, higher but tended to decrease with age as well. The total area of nuclei in the control group tended to decrease. In the first group with IVS, this process took place faster, while in the second group there was an increase of this value, which is indicative of a compensatory reaction of LV. With age the surface density of cardiomyocytes smoothly grew in all the groups. The nucleus-cytoplasmic ratio in LV gradually decreased with age in infants of all groups. More pronounced was this tendency in RV of TGA patients with IVS. Conversely, a slight increase

Studying the number density of capillaries revealed their simultaneous changes in both groups, with the highest point occurring at the age of 1 month in LV and RV in patients with

bromide.

up to 76.5+2.1 mm Hg.

in this ratio was noted in TGA patients with VSD.

IVS. Measuring the content of CE in groups with IVS and VSD resulted in the following findings. The content of Cu, Zn and Mn in the group with VSD is 1.3 – 1.5 times higher than in the group with IVS. The content of CE in LV and RV of patients with IVS was about the same, except for an increased content of Mn in LV. At the same time, the content of CE in RV of patients with VSD increased, compared with that in LV, notably higher were concentrations of Zn, Mn and, to a lesser extent, Cu, Cr, Br, Rb. These findings are also confirmed by the cardiometric data (see the Table). In the case of the type with IVS, hypertrophic processes in LV and RV develop uniformly, and CE concentrations in LV and RV do not differ essentially. In the second type of TGA with VSD, the right ventricle has to bear a large functional load, therefore, CE concentration in RV is higher than in LV. It agrees with more pronounced structural changes in coronary arteries in the functionally overloaded RV in patients with VSD. However, despite intensive cardiac work in the cases of ASD and VSD, oxygen delivery in this group of patients is worse because of lower blood oxygen saturation down to 32 %.

The reduction of the numeric content of total ions Ca2+ is caused by the development of hypertrophic phenomena in the myocardium of patients with congenital heart diseases (see Fig. 3A and 3B). Most probably, these hypertrophic phenomena result from a decrease in the number of myofibrils, which aggravates cardiac insufficiency.

Fig. 3A. Control group. Native sample of LV wall. A high level of fluorescence. Filter set 05. BP395-440nm. FT460. LP 470nm. Magnification 260. Staining with chlortetracycline.

Chemical Elements and Structural/Molecular

antibody FITS-conjugated.

Properties of Myocardium in Infants with Transposition of Great Arteries 345

Fig. 4. TGA with IVS (1 to 6 months). Sample of LV wall. Appearance of skeletal myosin granules in the myocardial structure. Filter set 09. BP395-440nm. FT460. LP 470nm. Magnification 260. Monoclonal Anti-Skeletal Myosin (FAST) Clone MY-32, secondary

Thus, considering the dynamics of intensity of the above morphological processes taking place in the myocardium of TGA infants not older than 1 year, it should be noted that hypertrophic changes in TGA patients' myocardium make progress with age. Hyperplastic processes associated with intensive polyploidization of the genetic material and an increase in the quantity of desoxyribonucleic acid play an important role in the remodelling of the heart in patients older than 6 months. On the basis of fluorometric measurement data, the decrease in the level of total calcium ions in cardiomyocytes of TGA patients is dependent on the occurrence of cardiosclerosis zones when hypertrophy of the myocardium is progressing. While adapting to these processes and to chronic hypoxia typical for congenital heart diseases and due to a less energy-consuming mechanism of skeletal muscle contractility, the synthesis changes over from cardiac myosin to a skeletal one, which, in turn, enhances clinical presentations of cardiac insufficiency because of a lowered speed of hypertrophied fibre contractility. In the case of hypertrophy of cardiomyocytes, not only is their volume (size) changed, but their phenotype as well. The synthesis of the ß-myosin (ß-МНС) heavy chain is activated and, simultaneously with suppression of α-МНС, the synthesis of cardio-specific proteins is changed over to proteins specific for skeletal muscles, for example, skeletal a-actin is expressed. This results in a reduction of the contractility speed of hypertrophied fibres. As hypertrophy proceeds, a few other genes are activated including some early growth regulators, genes responding to thermal shock and growth factors, as well as a gene of the atrial natriuretic factor, which facilitates a reduction in hemodynamic overload by regulating blood pressure and discharge of salt by the kidneys. Immunohistochemical examinations of the samples of TGA infants' myocardium made it

Fig. 3B. TGA with IVS (6 to 12 months). Native sample of LV wall. A lowered level of fluorophore fluorescence. Filter set 05. BP395-440nm. FT460. LP 470nm. Magnification 260. Staining with chlortetracycline.

In the case of hypertrophy not only is the volume (size) of muscle cells changed, but their phenotype as well. In the conditions of overload the contractile proteins in these cells are replaced by protein forms typical for foetuses and newborns. For example, the ß- myosin (ß-МНС) heavy chain is activated and, simultaneously with the suppression of α-МНС gene, the activity is changed over from the genes of the cardial α-actin to the genes of the skeletal one. This results in a reduction of the contractility speed of hypertrophied fibres. As hypertrophy proceeds, a few other genes are activated, including some early growth regulators, genes responding to thermal shock and growth factors, as well as a gene of the atrial natriuretic factor. The latter represents a peptide hormone that facilitates a decrease in hemodynamic overload by regulating blood pressure and salt discharge by the kidneys. Taking into account the preceding, we stained the myocardium samples with antibodies for Monoclonal Anti-Skeletal Myosin (FAST) Clone MY-32 skeletal myosin. As a secondary marker, we made use of FITS-conjugated secondary antibodies. As a result of the technique used, skeletal myosin was found in the myocardium of TGA patients (Fig. 4).

Fig. 3B. TGA with IVS (6 to 12 months). Native sample of LV wall. A lowered level of fluorophore fluorescence. Filter set 05. BP395-440nm. FT460. LP 470nm. Magnification 260.

used, skeletal myosin was found in the myocardium of TGA patients (Fig. 4).

In the case of hypertrophy not only is the volume (size) of muscle cells changed, but their phenotype as well. In the conditions of overload the contractile proteins in these cells are replaced by protein forms typical for foetuses and newborns. For example, the ß- myosin (ß-МНС) heavy chain is activated and, simultaneously with the suppression of α-МНС gene, the activity is changed over from the genes of the cardial α-actin to the genes of the skeletal one. This results in a reduction of the contractility speed of hypertrophied fibres. As hypertrophy proceeds, a few other genes are activated, including some early growth regulators, genes responding to thermal shock and growth factors, as well as a gene of the atrial natriuretic factor. The latter represents a peptide hormone that facilitates a decrease in hemodynamic overload by regulating blood pressure and salt discharge by the kidneys. Taking into account the preceding, we stained the myocardium samples with antibodies for Monoclonal Anti-Skeletal Myosin (FAST) Clone MY-32 skeletal myosin. As a secondary marker, we made use of FITS-conjugated secondary antibodies. As a result of the technique

Staining with chlortetracycline.

Thus, considering the dynamics of intensity of the above morphological processes taking place in the myocardium of TGA infants not older than 1 year, it should be noted that hypertrophic changes in TGA patients' myocardium make progress with age. Hyperplastic processes associated with intensive polyploidization of the genetic material and an increase in the quantity of desoxyribonucleic acid play an important role in the remodelling of the heart in patients older than 6 months. On the basis of fluorometric measurement data, the decrease in the level of total calcium ions in cardiomyocytes of TGA patients is dependent on the occurrence of cardiosclerosis zones when hypertrophy of the myocardium is progressing. While adapting to these processes and to chronic hypoxia typical for congenital heart diseases and due to a less energy-consuming mechanism of skeletal muscle contractility, the synthesis changes over from cardiac myosin to a skeletal one, which, in turn, enhances clinical presentations of cardiac insufficiency because of a lowered speed of hypertrophied fibre contractility. In the case of hypertrophy of cardiomyocytes, not only is their volume (size) changed, but their phenotype as well. The synthesis of the ß-myosin (ß-МНС) heavy chain is activated and, simultaneously with suppression of α-МНС, the synthesis of cardio-specific proteins is changed over to proteins specific for skeletal muscles, for example, skeletal a-actin is expressed. This results in a reduction of the contractility speed of hypertrophied fibres. As hypertrophy proceeds, a few other genes are activated including some early growth regulators, genes responding to thermal shock and growth factors, as well as a gene of the atrial natriuretic factor, which facilitates a reduction in hemodynamic overload by regulating blood pressure and discharge of salt by the kidneys. Immunohistochemical examinations of the samples of TGA infants' myocardium made it

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possible to observe the appearance of skeletal myosin in the cardiomyocytes. This testifies that, during hypertrophy development, the synthesis changes over from cardiac myosin to a skeletal one. Plain fluorescent microscopy of preparations stained with ethidium bromide revealed a drastic decrease in intensity of the fluorescent marker in infants aged under 6 months, as compared to the control group, and a rapid growth of ethidium bromide incorporation in infants aged 6 months and upward. It indicates a prevalence of the population of cardiomyocytes with diploid nuclei in the hearts of infants aged up to 6 months. In patients aged above 6 months, the heart remodelling process proceeds, with the processes associated with polyploidization of nuclear material and subsequent development of cell hypertrophy dominating. It should be emphasized that the level of polyploidization in LV cardiomyocytes is essentially higher than that in RV. Hence, the hyperplastic processes associated with intensive polyploidization of the genetic material and an increase in the quantity of desoxyribonucleic acid play an important role in the remodelling of the heart in patients aged above 6 months.

#### **6. Conclusion**

This study enabled us to come to the following conclusion on the development of a pathological mechanism causing the deaths of TGA patients at an early age. As a result of aorta and pulmonary artery transposition, low-oxygen venous blood flows into the systemic circulation system, limits the growth of newborns. The need for a sufficient volume of oxygen can be met only by increased load on the myocardium, with the development of heart hypertrophy uniform for LV and RV in patients with IVS and more pronounced in RV in patients with VSD. In this case the growth of TGA infants conforms to the age norm and even slightly exceeds it, while the body mass falls far short of the norm by 25-30 %. For hypertrophy and hyperplasia to develop dramatically, there should be an increased supply of nutritional and caloric substances, including CE. As the delivery of CE turns out to be insufficient, or their consumption increases, a 50 % deficiency of such microelements as Cl, Cr, Sr, Zn, Br, Rb and especially Se, which, as an active antioxidant, protects cardiomyocytes from lipid peroxidation, can be seen. As a consequence, structural disorders of the myocardium occur on the morphological/molecular level. Also observed are the following abnormalities: a decrease in the diameter of muscle fibres and the average area of nuclei, a drop in the level of the total calcium ions against the background of intensive polyploidization of genetic material, an increase in the content of the quantity of desoxyribonucleic acid, and change from the cardiac myosin synthesis over to a skeletal one. All these changes lead to alteration of the myocardium, occurrence of cardiosclerosis, development of cardiac insufficiency and reduction of arterial blood saturation down to 32 % and below, which is fatal, and results in death of the organism. This is a picture of TGA development pathogenesis of infants from neonatal age up to 1 year old. In this case, only definitive repair of the disease can break the pathogenetic chain of TGA in an early period, and the best time when effective cardiac surgery could be performed for TGA infants is in the neonatal period.

We suppose, that to prevent the development of congenital heart diseases including TGA, pregnant women and nursing mothers should get the optimum quantity of microelements Cr, Zn, Sr, Ni, Rb, Br and most of all Se, protecting the myocardium from lipid peroxidation.
