HEMODYNAMICS AND CARDIAC CONTRACTILE FUNCTION IN TYPE 1 DIABETES.

The cardiohemodynamics was studied 1 week after the administration of streptozotocin (60 mg / kg) or 2 weeks after a dose of 30 mg / kg. All rats had a significantly elevated level of glucose in the blood (up to 27-31 mM). In an echocardiographic study, about 1/3 of diabetic animals exhibited systolic dysfunction, and the remaining 2/3 - diastolic dysfunction with an increase in isovolumic relaxation time by 1.5 times. The catheterization of the left ventricle (LV) with a sensor that allows simultaneous measuring LV pressure and volume in both groups revealed decreased cardiac output by 25-31% and maximal ejection rate by 34-50%. However, LV developed pressure, the maximal rate of its development and the level of blood pressure remained within the control values, thus reduced LV ejection rate was probably due to increased arterial stiffness - a negative correlation was found between these indicators (r = - 0.70). The diastolic dysfunction group differed from systolic dysfunction by a significantly smaller end diastolic volume by 22%. Thus, in type 1 diabetes, LV remodeling with reduced end diastolic volume allows to maintain a normal ejection fraction in the presence of distinct heart failure.

Normalisation of diabetic heart pump function at decreased functional load.

Aim      To study left ventricular (LV) hemodynamics in presence of decreased blood inflow to the heart as well as changes in myocardial content of energy metabolites in diabetic rats.Material and methods  Diabetic cardiomyopathy is characterized by impaired heart contractility and by transition of cardiomyocyte energy metabolism fatty acids exclusively as a source of energy. This reduces the efficiency of energy utilization and increases the heart vulnerability to hypoxia. This study was performed on rats with type 1 diabetes mellitus induced by administration of streptozotocin (60 mg/kg). The LV pump function was studied with a catheter that allows simultaneous measurement of LV pressure and volume in each cardiac cycle.Results Blood glucose was approximately sixfold increased at 2 weeks. Heart failure was detected with decreases in ejection fraction by 27%, minute volume by 39%, and stroke work by 41%. Systolic dysfunction was based on a decrease in LV peak ejection velocity by more than 50%. Furthermore, the LV developed pressure and contractility index were within the normal range, while 1.5 times increased arterial stiffness was the factor that hampered ejection. The sum of adenine nucleotides was decreased by 21%, the ATP content was decreased by 29%, and also creatine phosphate formation was reduced in the myocardium of diabetic rats. Lactate content in the diabetic myocardium was increased almost threefold, which indicated mobilization of aerobic glycolysis. With the reduced preload, equal diastolic volume (0.3 ml), and equal blood pressure (60 mm Hg), the diabetic heart pump function did not differ from the control.Conclusion      In type 1 diabetes mellitus, decreases in functional load and oxygen consumption normalize the myocardial pump function with disturbed energy metabolism.

Systolic Dysfunction of the Heart in Type 1 Diabetes Mellitus.

Impaired insulin synthesis is accompanied by hyperglycemia and the development of diabetic cardiomyopathy. Echocardiography and left-ventricular catheterization were employed for studying the contractile function of the left ventricle in 2 weeks after administration of streptozotocin (60 mg/kg). The results obtained by both methods were similar and indicated the development of systolic dysfunction with a 27% decrease in cardiac output. The invasive study showed that the maximum rate of left-ventricular pressure development, the contractility index, and systolic left-ventricular pressure were within the normal range, but the peak ejection rate was reduced by 28%. BP was normal, but the vascular stiffness index was increased by about 1.5 times and inversely correlated with the peak ejection rate (r=-0.69). The results showed that systolic dysfunction in type 1 diabetes model was due to reduced ejection from the left ventricle at normal rate of left-ventricular pressure development.

Compensatory Changes of the Diastole under Conditions of Inflow Restriction to the Heart.

This work was designed to study changes in the mechanical properties of rat myocardium during short-term (2-3 sec) compression of the lower vena cava. A catheter was inserted into the left ventricle, allowing simultaneous measurement of left-ventricular volume and pressure. The decrease in the left-ventricular end-diastolic volume caused by inflow restriction was accompanied by less pronounced decrease in the left-ventricular stroke volume and maximum rate of left-ventricular pressure development. This was coincided with accelerated relaxation and deeper fall of the minimum left-ventricular diastolic pressure. The lower was left-ventricular end-systolic volume, the greater was the degree of these changes. It is assumed that the "restoring force" that naturally appears under conditions of low filling of the left ventricle is determined by elastic N2B part of the titin molecule that is compressed during strong shortening of myofibrils and accelerates their return to the previous length during relaxation. As a result of better filling of the left ventricle, the heart can maintain left-ventricular stroke volume at the appropriate level.

[Prevention of Diastolic Dysfunction Caused by Doxorubicin by Mitochondrial Antioxidant Plastomitin].

Aim      An attempt to prevent the development of diastolic dysfunction (DD) with the mitochondrial antioxidant plastomitin on a model of doxorubicin-induced cardiomyopathy. DD is a type of chronic heart failure. Due to the increasing number of patients with this condition and the absence of effective therapy, development of means for DD correction is a relevant objective.Material and methods  Cardiomyopathy was modeled in 17 rats by two subcutaneous injections of doxorubicin 2 mg/kg/week. The other group (n=17), also administered with doxorubicin, received plastomicin 0.32 mg/kg daily subcutaneously. Left ventricular function was evaluated with echocardiography (EchoCG) and cardiac catheterization with simultaneous pressure and volume monitoring.Results According to EchoCG data the ejection fraction remained unchanged in the experimental groups. Cardiac catheterization showed disorders of both myocardial contractility and relaxability only in the doxorubicin group.Conclusion      A course of plastomitin in combination with the doxorubicin treatment can maintain normal heart contractility and thereby, prevent the known doxorubicin cardiotoxicity.

[Early changes of energy metabolism, isoformic content and level of titin phosphorylation at diastolic dysfunction].

RELEVANCE:  Diastolic dysfunction occurring at hypertension, obesity, diabetes, or treatment with doxorubicin tends to prevail in all patterns of chronic heart failure. Lack of effective therapy forces to look more into the metabolic processes in cardiomyocytes. OBJECTIVE:  Assess energy metabolism in cardiomyocytes and changes in titin, a giant myofibril protein that responsible for their elasticity. MATERIAL AND METHODS:  The study model was cardiomyopathy occurring after the 4-week administration of doxorubicin (2 mg/kg weekly). Diastolic dysfunction was identified by echocardiography and catheterization with the simultaneous measurement of pressure and volume of the left ventricle (LV). RESULTS:  The levels of adenine nucleotides and phosphocreatine in the heart of animals treated with doxorubicin differed little from the normal values, but lactate levels were increased manifold. A 50% increase in the level of titin phosphorylation was detected, which correlated (r = 0,94) with a nearly twofold increase in the share of a more elastic N2BA-isoform of this protein. CONCLUSION: This form of diastolic dysfunction involves the activation of anaerobic metabolism and increased stretching of myofibrils facilitating LV filling.

[Mitochondrial Antioxidant Plastomitin Improves Cardiac Function in Doxorubicin-Induced Cardiomyopathy].

The aim of the study was to ascertain whether the use of plastomitin, the mitochondrial antioxidant, can affect the development of systolic dysfunction that occurs in rats after 4 weeks of doxorubicin treatment (2 mg/kg weekly). Materials and methods. Male Wistar rats weighing 320-380 g were used in this work. Echocardiographic study was carried out using Vevo 1100 with linear probe 13-24 MHz frequency. Results. Echocardiographic study of rats through 8 weeks from the beginning of doxorubicin treatment showed the presence of systolic dysfunction with decrease of ejection fraction of the left ventricle (LV) by 32%. Hearts of rats, to which plastomitin (0.32 mg/kg daily) was administered simultaneously with doxorubicin, showed significantly increased ejection fraction and shortening fraction as compared with doxorubicin group, and these values were close to the control. In experiments with simultaneous registration of LV pressure and volume, it was found that the hearts of all rats treated with doxorubicin showed reduced contractility index and stroke work, while maintaining normal cardiac output. Such compensation in experiments with treatment with doxorubicin alone was achieved through significant reduction in the peripheral resistance, slowing of myocardial relaxation, and facilitation of LV diastolic filling during prolonged diastolic pause (the heart rate was slowed by 23%). In experiments with simultaneous application of doxorubicin and plastomitin, the compensation was achieved through preservation of myocardial contractility and relaxability, the heart rate and peripheral resistance. This method of compensation is more beneficial for the body, because it does not restrict the supply of organs and tissues with oxygen, and has significant advantage over doxorubicin group at equal heart rate. Conclusion. The results allow to conclude that the use of plastomitin together with doxorubicin prevents the development of doxorubicin-induced systolic dysfunction.

[The Time Course of Formation Of Systolic Dysfunction of the Heart in Doxorubicin Cardiomyopathy].

The anthracycline-induced cardiomyopathy is a frequent and menacing complication of antitumor therapy leading to chronic heart failure. A study of the formation of heart failure can reveal early signs of the development of systolic dysfunction of the heart. In this work in rats we studied cardiac function at different duration of doxorubicin treatment, the most effective anthracycline antibiotic. Cumulative doses of doxorubicin were 8-20 mg/kg, and the term of study lasted from 6 to 20 weeks. The echocardiography and catheterization of the left ventricle (LV) have been use. The ejection fraction and other indicators of LV contractility decreased steadily with increasing dose and duration of the study, in parallel with rat survival. However, the cardiac output related to the unit of body weight, as well as diastolic LV size, remained at a level close to control within 8-10 weeks. Only after 20 weeks when the ejection fraction decreased from 81+/-1 to 49+/-4%, diastolic LV volume increased by 59%. Invasive indicators of myocardial contractility and relaxability significantly decreased by 11 and 19% after doxorubicin dose of 8 mg/kg, while time of preejection and time of systole increased by 18 and 10%. These changes progressed with increasing doses of doxorubicin. At each dose, the relaxation constant declined relatively deeper than contractility index by 8-25%. The results show that: 1) the gradual formation of cardiac insufficiency mobilizes a variety of compensatory mechanisms that retard cardiac dilatation; 2) the development of systolic dysfunction takes place with a predominantly violation of relaxation process; 3) an elongation of the preejection period and duration of systole may serve as noninvasive criteria for the formation of the systolic dysfunction.

[The Action of Apelin-12 and Its Analog on Hemodynamics and Cardiac Contractile Function of Rats With Isoproterenol-Induced Myocardial Lesion].

Introduction of isoproterenol (beta-adrenoreceptor agonist) into rats is one of the widespread experimental models of heart failure. It is caused by diffuse ischemic damage of cardiomyocytes, followed by development of substitutive fibrosis. Apelin is a natural regulator of the myocardial contractility. The effects of apelin molecule fragment, apelin-12 and its more stable synthetic analogue, apelin-12-2 on cardiac contractile function of rats with isoproterenol-induced myocardial lesion (IML) and control animals has been studied in this work using invasive (catheterization of the left ventricle) and non-invasive (echocardiography and impedansometry) methods. Infusion of both peptides was made by sequentially increasing rate from 0.5 to 50 µg/kg/min. In the control group, efficacy of apelin-12 was low while apelin-12-2 moderately but significantly increased indices of myocardial contractility and relaxability. These changes were more pronounced in rats with IML and, in addition, the heart rate and LV systolic pressure increased in this group. These results correlate well with echocardiographic studies which showed increases of LV end diastolic volume, stroke volume and ejection fraction by 17-38%. These alterations are probably due to improved Ca2+ transport in cardiomyocytes, as in experiments on isolated cardiomyocytes both apelins have facilitated and improved Ca2+ removal from myoplasma. The results allow to conclude that apelin-12-2 seems to be a promising candidate for further development as a therapeutic agent in heart failure.

[Cardiotropic action of oxacom in experimental heart failure].

Prolonged hypotensive effect of oxacom (dinitrosyl iron complexes with ligand glutathione) has been well documented in animals and healthy volunteers, but effect on the heart is not defined. In this work, the blood pressure (BP), and the pressure in the left ventricle (LV) were recorded in rats. Intravenous bolus injection of oxacom (10 mg/kg) caused an immediate average BP decrease by 20-30 mm Hg followed by a slow recovery. The LV systolic and diastolic pressures did not change, but the maximal speed of pressure development, and contractility index at peak action of oxacom increased by 26-33%, while isovolumic relaxation constant fell by 30%. These changes gradually normalized within 10-15 minutes. Effect of oxacom on hearts with isoproterenol-induced diffuse ischemic myocardial lesions and diastolic heart failure was similar to that observed in the control group except the isovolumic relaxation constant rose 1.5-fold while elevated LV diastolic pressure fell. Results suggest that oxacom exerts the positive cardiotropic action especially at heart failure.

[Some aspects of heart rate variability estimation in rats].

This study focuses on researching of heart rate variability (HRV) in rats with autoimmune myocarditis. Intact rats were investigated additionally. It was registered 2-, 5- and 20-min duration ECG from awake animals at rest-conditions and after cooling probe (CP), and then time domain and spectral parameters of HRV were calculated. We shown that 1) after CP decreasing of parasympathetic influence and augmentation of sympathetic influence on heart rate regulation in rats with autoimmune myocarditis was more manifested than in intact rats, 2) in CP with the 5-min ECG interval's duration was more informative for HRV estimation, 3) intracardiac inflammation leads to modification of correlation interconnection between some HRV-parameters, and that may talk about features of heart's chronotropic regulation in rats with autoimmune myocarditis.

[Complex study of the rat heart at isoproterenol damage].

Introduction of isoproterenol (an agonist of beta-adrenoreceptors) to rats is one of the widespread experimental models of cardiac failure. It is caused by damage of cardiomyocytes with the subsequent development of substitutive fibrosis. The purpose of the given work was the complex characteristic of cardiac function by means of invasive and noninvasive (echocardiography and impedansometry) methods of research. Isoproterenol was injected twice with a daily interval in dozes 85, 120, 150 or 180 mg/kg. Echocardiographic study of the heart in 2 weeks revealed obvious attributes of cardiac failure (left ventricular dilatation, lowered ejection fraction) in the groups which have received high cumulative dozes of isoproterenol (300-360 mg/kg). The catheterization of the left ventricle in these groups has shown raised enddiastolic pressure, decreased maximal rate of pressure development and fall, and also lowered indices of myocardial contractility and relaxability. In the groups which have received smaller isoproterenol dozes, apparent decrease in relaxability parameters (constants of isovolumic and auxovolumic relaxation) has been revealed at only slightly changed parameters of contractility. A strong correlation between echocardiographic and invasive parameters of myocardial contractility has been found. The phase analysis of the cardiac cycle has shown a lengthening of isometric phases of contraction and relaxation, as well as duration of ejection due to shortening duration of filling of both ventricles. Cardiomyocytes isolated from hearts with obvious cardiac failure responded to electrostimulation by arrhythmic contractions and also by much slowed and incomplete removal of free Ca++ from the myoplasm. Results allow to conclude that relatively smaller extent of myocardial damage is accompanied by decreased relaxability at slightly changed contractility, while at greater degree of damage both processes fail, but delay of relaxation still prevails.

Age-dependent and 'pathologic' changes in ICG waveforms resulting from superposition of pre-ejection and ejection waves.

Impedance cardiography (ICG) is a popular bioimpedance application used for the non-invasive evaluation of the left ventricular stroke volume and contractility. It implies the correct determination of ejection start and end points and the amplitudes of certain peaks in a differentiated impedance cardiogram. An accurate identification of ejection onset by ICG is often problematic, especially in cardiologic patients, due to the peculiar character of the waveforms. A simple theoretical model was employed to test the consequences of the hypothesis that two major processes can contribute to the formation of an impedance systolic wave: (1) the pre-ejection changes in heart geometry and the surrounding vessels produced by ventricular contraction during the isovolumic phase, and (2) the expansion of aorta and adjacent arteries during the ejection per se. The former process initiates the pre-ejection wave while the latter triggers the ejection wave, both of which contribute to the impedance pulse waves associated with the heartbeats. A new two-bell model predicts a potential mechanism responsible for the abnormal shapes of ICG derivative dZ/dt due to the presence of the pre-ejection waves and explains the related errors in systolic time intervals and amplitude parameters derived from such ICG waveforms. It also advances an alternative viewpoint on the nature of the dZ/dt B-point notch. An appropriate decomposition method opens a promising way to avoid the masking effects of these waves and to correctly determine the onset of ejection as well as the corresponding peak amplitudes from the 'pathologically shaped' ICG signals.

[Dynamics of heart rate changes in rats following stepwise change of treadmill running speed].

Amplitude and temporal responses of heart rate to stepwise increase or decrease of treadmill running intensity were investigated in rats. Heart rate amplitude response was shown to be connected mainly with the change of sympathetic nervous activity whereas heart rate temporal response was shown to be determined predominantly by parasympathetic cardiotrophic influences.

[Historical sketches on classical physiology of the heart: the initial phase of systole].

Crucial physiological advances in the phase analysis of cardiac performance with respect to their historical and biographical aspects are elucidated. The described period started from the early measurement of blood pressure (1733) and the first graphical representation of cardiac performance (1861), continued by the progress in recording of cardiac electrical activity and a detailed study of the consecutive events throughout the cardiac cycle (1921) and, finally, reached the recording of changes in the left ventricular dimensions and shape during the phase which precedes the start of blood ejection (1955-2005).

[Contractility of the left ventricle of the human heart noninvasive measurement in each cardiac cycle].

History of development of the method of measurement of duration of the preejection (DPE) period - characteristic of left ventricular (LV) contractility is presented. On the basis of physiological prerequisites a novel computerized method of DPE measurement in each consecutive cardiocycle has been created. Distinct features of this method are: 1) principle of measurement - tetrapolar impedancemetry, with signal electrodes located along projection of the ascending aorta, one in the center of presternum, second - 5 cm caudally; 2) starting point for DPE counting - the point on ascending portion of R wave of electrocardiogram at which the first derivative of ECG signal reaches maximum, stopping point - the point of maximum of the second derivative of the primary impedance signal on the ascending front of its pulse wave. The method has been tested on healthy people for 10 functional tests. The results are presented characterizing dynamic peculiarities of changes of LV contractility during veloergometer exercise test with staderly increasing work load and reflecting development of positive inotropic action of sympathetic nervous system. Special characteristics of this action: small concealed period, preservation of achieved elevated level during lowering of work load (before its switching off) and subsequent slow (compared with chronotropic effect) diminution, as well as turning on at low loads.

[Pre-ejection period as a cardiac cotractility index: noninvasive beat-by-beat evaluation in the human study].

Beat-by-beat evaluation of left ventricular contractility provides and insight to the current dynamics of cardiac control. In non-invasive studies, pre-ejection period is conventionally used as an index of contractility. Pulse waves of electrical impedance (deltaZ) reflect the systolic dilations of the aorta segment confined between the properly placed signal electrodes. The relation of B-wave in the differentiated signal dZ/dt to the dalation of the aortic root prior to the start of ejection is discussed. The previous findings and our own experience indicate that the conventional method of identification of the end of the pre-ejection period by the B-point is not suitable for its reliable determination in each cardiac cycle. Instead of this, we defined the start of election by the maximum of the d(2)Z/dt2 signal associated with maximum acceleration of the ascending aorta dilation during the early ejection phase. It can be reliably found beat-by-beat. The proposed technique was successfully aplied for monitoring of fine dynamics of pre-ejection period changes during Valsalva maneuver, as well as in active and passive orthostatic tests.

[Computer cardiokymography. On its way to long-term noninvasive monitoring of cardiac performance in daly life]. / Komp'iuternaia kardiokimografiia na puti k dlitel'nomu neinvazivnomu nabliudeniiu za sokratil'noi deiatel'nost'iu serdtsa cheloveka.

A functioning heart generates low-frequency and low-amplitude movements (up to 40 (mrn) of soft tissues in the percardial area. Since the 1950-s of the XX-th century cardiologists have studied these movements to employ them in the diagnostics of ischemic heart disease (IHD). Indeed, changes of the movements have found their diagnostic application in this field. If blood supply to a certain area of ventricular myocardium is insufficient the contractions in this area diminish and even ceases. After systolic increase in ventricular pressure this area dilates and forces intercostal tissues out, causing a "bulge" wave on the record. For recording the patient must be in supine position and hold the breath. High frequency electromagnetic field generator was used in an attempt to examine the heart movements. It was found that such instrument measures the thickness of the air-gap that serves as a dielectric or a "capacitor" which forms between the skin and approaching it flat inductive coil. Nevertheless, such an instrument (cardiokymograph, CKG) can reveal changes in contractions of ischemic myocardium and markedly increases the sensitivity of the exercise ECG test. However, CKG can be recorded only after termination of the test. This principal disadvantage has been overcome by software that allowed the recording of CKG during the test. A low-frequency capacitance transducer developed recently by Chinese researchers has provided a simultaneous recording of several CKG. After modifying the transducer, we have established that 1) the shape of CKGs is the same as that CKGs recorded by all our predecessors, 2) CKGs are reproducible even within a 3-month interval, 3) the enormous mechanical interference caused by respiratory movements and, to a greater extent, by the vigorous movements of the legs and trunk during veloergometry can be eliminated by digital processing of the transducer signals, and 4) pathological changes appear in CKG of patients with IHD, which enables one to stop veloergometry at lower loads, thus increasing the safety of the test. Since for large medical insurance companies very simple and inexpensive cardiokymograph are quite unprofitable, their commercially production in USA and in Germany has been stopped. However, the goal of cardiokymography: a real-time, beat-to-beat, long-term monitoring of cardiac function in daily life, remains the major factor determining the future of the method.

[Effect of radio frequency catheter ablation on spectral parameters of heart rate variability in patients with paroxysmal supraventricular tachyarrhythmias]. / Vliianie radiochastotnoi kateternoi ablatsii na spektral'nye pokazateli variabel'nosti ritma serdtsa u bol'nykh s paroksizmal'nymi nadzheludochkovymi takhiaritmiiami.

AIM: To assess effect of radio frequency catheter ablation (RFCA) on heart rate variability (HRV) in patients with supraventricular tachyarrhythmias (SVT). METHODS: Spectral analysis of HRV on 5-minute ECG strips was carried out in 19 patients with SVT before and 2 days after RFCA. RESULTS: Both total and high frequency power significantly decreased (p<0,05) after RFCA in supine and orthostatic positions. Significant decrease of low frequency power occurred after RFCA in orthostatic position. CONCLUSION: In patients with SVT RFCA alters autonomic regulation of chronotropic function of the heart. Sympathetic and parasympathetic influences on the chronotropic function of the heart are attenuated in early period after the procedure.