Method for preventing anthracycline cardiotoxicity in patients with breast cancer

FIELD: medicine.

SUBSTANCE: in the patients diagnosed with breast cancer and recommended to have a chemotherapeutic course, the heart rate is measured one week before the treatment according to electrocardiography after a 5-minute rest. If the measured heart rate is 70 beats per minute or more, ivabradine is prescribed in a daily dose of 10 mg. Electrocardiography is repeated after a 5-minute rest 4 weeks later. If the measured heart rate is 70 beats per minute or more, the dose is titration is made to 15 mg a day. If the measured follow-up heart rate is less than 70 beats per minute, the daily dose is kept at 10 mg. If the initial heart rate is less than 70 beats per minute, trimetasidine is prescribed in a daily dose of 70 mg for the whole period of treatment independent from the further heart rate measurement. All the patients take the preparation throughout the duration of 6 months.

EFFECT: method enables reducing the cardiotoxic action of the anthracycline chemopreparations in the patients with breast cancer.

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The invention relates to the field of medicine, namely cardiology, and can be used for prevention of cardiotoxicity of drugs anthracyclines chemotherapy in patients with breast cancer.

Breast cancer is the most common cancer in women, taking in the structure of morbidity of 16% [1].

Chemotherapy, along with surgical and radiation therapy, is one of the components that significantly reduce the mortality of patients with breast cancer. Drugs anthracyclines (doxorubicin, epirubicin) are among the most effective for the treatment of breast cancer and included in most standard chemotherapeutic treatment for this disease [2].

However, their active clinical use is limited by cumulative and dose-dependent cardiotoxic effects, which may lead to asymptomatic systolic dysfunction, and the expanded chronic heart failure (CHF), accompanied by a significant decrease in the quality of life and extremely poor prognosis [3, 4]. New chemotherapy drugs for breast cancer treatment also adversely affect the cardiovascular system [5]. These include taxanes, alkylating and�patients under stood, antimetabolites and some of the new targeted therapy drugs, such as trastuzumab, bevacizumab and the tyrosine kinase inhibitor is sunitinib [5-8]. Radiation therapy for breast cancer can also lead to heart disease, however, associated changes, are identified, usually years after exposure [5]. With the increase in the number of patients with breast cancer and increased survival of patients, the impact of cancer treatment on the cardiovascular system is becoming more important.

The risk factors for the development of cardiotoxic action of chemotherapeutic treatment include chemotherapy regimen, as well as age, obesity, physical inactivity, the presence of cardiovascular disease [5].

The mechanism of toxic effects of anthracycline different from their therapeutic mechanism and is due to multiple effects on cardiomyocytes, including apoptosis, changes in iron homeostasis, dysregulation of calcium homeostasis, and mitochondrial dysfunction [9]. Another mechanism of heart damage by anthracyclines is the activation of lipid peroxidation [10]. Stand-alone models of cardiomyocytes long time, it was shown that doxorubicin reduces the concentration of intracellular adenosine triphosphate (ATP) and phosphocreatine (FC) more than 50% � for 24 h [11] and 20% with the introduction of effective dose the corresponding 70-minute infusion [12]. Similar results were obtained in vivo by magnetic resonance spectroscopy [13]. A reduction in the levels of FC and the ratio of PCR/ATP was observed within several days after administration of a single high dose of doxorubicin, and after a few injections of lower doses. It is important to note that long-term accumulated effects of lower doses of doxorubicin and were more pronounced than acute effects equivalent single dose. It is curious that, according to magnetic resonance spectroscopy, a decrease in the ratio of PCR/ATP is preserved even in patients 4 years after the end of chemotherapy [14]. More than 90% of ATP used by the cells, is produced during mitochondrial respiration. Already in the early stages doxorubicine cardiotoxicity develop the characteristic pathological changes of mitochondria. Prolonged exposure of doxorubicin on isolated myocardial mitochondria leads to rapid disruption of oxidative mitochondrial processes [15]. To explore the effects of doxorubicin on the metabolism of oxygen in the myocardium of patients was used positron emission tomography [16].

Other targets of doxorubicin that can potentially interfere with oxidative ATP production, are �elcova-lipid complexes involved in the transfer of ATP and FC from mitochondria into the cytosol. There are several studies that suggest that doxorubicin promotes the deterioration of the function of these complexes. Doxorubicin affects denisedenise Transporter 1, isoform, which is predominantly found in the heart, and the inorganic phosphate Transporter, homolog denisedenise vector [17], and also interferes with the normal function of mitochondrial creatine kinase.

It should be added that doxorubicin, in addition to running functional changes, regulates the participation of a number of mitochondrial enzymes in respiration and oxidative phosphorylation.

The heart is able to utilize different substrates to ensure their high energy needs. Under normal conditions, the preferred substrates are fatty acids (FA) ensuring the establishment of 60 to 80% of all ATP in the myocardium. However, the oxidation of the LCD to generate a certain amount of ATP required approximately 10% more oxygen than the oxidation of glucose [18].

When using cell cultures in animal experiments it was found that doxorubicin affects the metabolism of fatty acids in the heart [19]. When doxorubicin treatment increases the level of the LCD in the serum [20]. Doxorubicin inhibits the oxidation of palmitate, DL LCD�the auditors of the chain. As a possible mechanism was proposed damage carnitinelongevity-1 and/or depletion of L-carnitine. In cardiovascular diseases, at least in their early stages, the attenuation of lipid peroxidation was accompanied by increased utilization of glucose as a compensatory mechanism. When treated with doxorubicin, the situation is different. Cardiomyopathy induced by doxorubicin, is associated with lower utilization of each of the substrates, as the LCD and glucose [21].

Induced by doxorubicin violation of systolic left ventricular function is associated with early changes in sympathetic-parasympathetic balance toward the predominance of sympathetic tone. Epirubicin has less cardiotoxicity when calculating the dose, in comparison with doxorubicin, which allows the use of higher cumulative doses of the drug to achieve the threshold of cardiotoxicity (900 mg/m2in comparison with 450 mg/m2for doxorubicin). However, to obtain comparable with therapeutic effect of doxorubicin, epirubicin should be used in higher doses (25-50%). In accordance with the conducted metanalisis clinical studies difference between these two drugs in the risk of developing CHF is not obtained [22].

In Russia for defined�I cardiotoxic effects of chemotherapy is traditionally used for ECG, not possessing sufficient sensitivity for early detection of heart damage. The recommendations of the European society of oncologists 2009 [23] to monitor the status of patients in addition to ECG are encouraged to actively use echocardiography as the original denition of systolic and diastolic function for all patients prior anthracycline chemotherapy with risk factors for CVD (Smoking, dyslipidemia, obesity), or over 60, or cardiovascular disease (AT, DM, IHD, etc.), or previous irradiation area of the mediastinum; for all patients prior monoclonal antibody therapy (trastuzumab).

Repeated echocardiography shows after performing ½ total dose of doxorubicin or until a total dose of doxorubicin 300 mg/m2(older than 60 years at the dose of 240 mg/m2). Also recommended follow-up Echocardiography examination at 3, 6 and 12 months after therapy with anthracyclines. Periodic Echocardiography examination (every 3 months) is recommended in patients on therapy with monoclonal antibodies.

Most attention in the recommendations under echocardiographic monitoring is paid ejection fraction (EF) of the LV. The decrease in LVEF of more than 20% from baseline or any reduction less than 50% requires a review of therapy, the purpose of cardio-soudes�s products and active surveillance. It should be noted that in some clinical trials with monoclonal antibodies was used a stricter definition of cardiotoxicity [24]: a decrease in LVEF by more than 5% to less than 55% in combination with symptoms of heart failure or a decrease of more than 10% to less than 55%.

However, due to the pathophysiological mechanism of cardiotoxicity of doxorubicin reduction in LVEF occurs only when a significant amount of damaged cardiomyocytes.

Along with echocardiographic assessment of systolic and diastolic function of left ventricle in early diagnosis of cardiotoxicity can be used different biomarkers. So even a small increase in TnI after the administration of chemotherapy is considered to be a powerful indicator of damage to the left ventricle and poor prognosis [25]. In addition, it can be used to predict the subsequent development of systolic dysfunction of the left ventricle at a very early stage. According to D. Cardinale et al. the increase in troponin (cTnI) is seen in 32% of patients on therapy with anthracyclines [14]. In this case the measurements were carried out serially through 12, 24, 36 and 72 hours after administration of the drug. Appeared data and about the possibility of using high-sensitivity troponin I (increased to 30 ng/ml) for the diagnosis of cardiotoxicity [26].

IP�Ong the prevalence of chronic cardiotoxicity is difficult to determine due to varying definitions of cardiotoxicity and as a rule, insufficient follow-up period in clinical trials.

Data from clinical trials indicate that the prevalence of CHF is 3.0% of patients receiving a cumulative dose of doxorubicin 400 mg/m2the probability increases to 7.5% at a total dose of 550 mg/m2and to 18.0% at 700 mg/m2[27]. When combined therapy with doxorubicin and trastuzumab myocardial dysfunction develops in 27% of cases [28]. Older patients (older than 67 years), the incidence of cardiomyopathy in three years after treatment, reaching 42% [29].

In long-term prospective study in 120 patients with advanced breast cancer, in patients who received high cumulative doses of epirubicin (850-1000 mg/m2) the risk of developing CKD was 11% after 1 year after therapy, and after 5 years - 20% [30].

To date not carried out large-scale special studies on the treatment of patients with anthracycline cardiomyopathy. The prognosis of patients with anthracycline cardiomyopathy is significantly more severe than other causes of reduced LV systolic function. In earlier studies, one-year mortality in patients with anthracycline cardiomyopathy reached 50% [31]. Treatment of patients with extensive CHF clinic is conducted in accordance� General recommendations for the treatment of patients, although the evidence base for this is weak. Regarding interventional techniques evidence indicates that transplantation of cardiac and resynchronization therapy, effectine in anthracycline cardiomyopathy than in other non-ischemic cardiomyopathies [32, 33].

From drug therapy there are few studies about the improvement of clinical status and LV contractility on a background therapy of ACE inhibitors and beta-blockers. So in a study of 25 patients with anthracycline cardiomyopathy, significant improvement in LVEF was observed only in combination therapy with ACE inhibitors and beta-blockers (26±10.0% to 37±17.6%, p<0.019) [34]. The study D. Cardinale, the 201 patients with EF<45% on the background of chemotherapy appointment of the combination of enalapril and carvedilol resulted in recovery of LV function in 42% of patients [35]. The response to therapy was directly dependent on time of initiation of therapy. None of the patients with reduced left ventricular ejection fraction more than 6 months of response to therapy were noted.

Even less data on the effectiveness of cardiovascular drugs in the prevention of cardiotoxicity. So in a randomized study in 50 patients 6-month prescription of carvedilol at a daily dose of 12.5 mg prevented the decrease in LVEF in the background of hemoterapia, while in the control group, LVEF decreased by 1% [36]. The same group of authors have shown that a six-month prescription of nebivolol at a dose of 5 mg per day interferes with the growth of the DLC LV and brain natriuretic peptide [37]. In an open randomized trial D. Cardinale et al. the appointment of enalapril during the year patients with increased troponin I during chemotherapy prevented the decrease in LVEF, whereas in the control group significant decrease in LVEF was observed in 43% of patients [38]. On the other hand in a three-year prospective study in 147 patients with lymphoma were found protective action of enalapril and metoprolol [39].

It is now established that the high frequency of heart rate (HR) is an independent risk factor total, sudden and cardiovascular mortality [40, 41]. On the one hand, HR is a major determinant of myocardial oxygen consumption and duration of diastole significantly affect coronary blood flow. Relatively recently, it was shown that high heart rate is an independent long-term predictor of death from cancer with the greatest risk at a heart rate of>73 beats per minute [42].

Ivabradine is an innovative drug, the mechanism of action is associated with selective inhibition of f-channels in cells of the sinus node. They are activated when hyperpo�arizala and is a key regulator of the rate of spontaneous diastolic depolarization. Selective blockade of the If currents under the action of ivabradine leads to the slowing of the resting heart rate, and decrease tachycardia in response to the activation of sympatho-adrenal system without additional lowering of blood pressure [43]. The mechanism responsible for its anti-anginal and anti-ischemic effect.

Increasing the time of filling of the ventricles and the preservation of myocardial contractility observed in the use of ivabradine in combination, lead to a significant increase in stroke volume of the heart. By increasing the stroke volume ivabradine is able to maintain the proper level of cardiac output [44].

The efficacy and safety of ivabradine in patients with stable CAD confirmed in several large-scale studies [45].

In 2010 published the results of a large study SHIFT, which examined the efficacy and safety of ivabradine in patients with CHF and severe LV systolic dysfunction [46]. The addition of ivabradine to optimal CHF therapy led to a decrease in cardiovascular mortality and hospitalizations in the context of heart failure by 18%.

Although the primary mechanism of action of ivabradine in coronary artery disease and heart failure is considered a selective decrease in the heart rate, to date there is evidence of beneficial effects of ivabradine on indices of oxidative stress and dysfunction e�datele. So in the publication it was shown that treatment with ivabradine for 20 weeks leads to decrease of reactive oxygen species and restoration of endothelial function in animals with dyslipidemia [47]. Reducing the formation of reactive oxygen species and of lipid peroxidation during therapy with ivabradine has been shown previously by an independent group of researchers [48]. The same group of authors published in the European journal of cardiology study that showed not only improvement of endothelial function during therapy with ivabradine, and the consequent formation of collaterals [49].

On the other hand, the appointment of ivabradine leads to the restoration of diastolic LV function and reduction of fibrosis of the myocardium of the ventricles and Atria [50]. In a pilot study with a model of heart failure on the background infusion of angiotensin II has been shown that treatment with ivabradine, but not metoprolol, prevents the development of heart failure by reducing processes of fibrosis, inflammation and apoptosis [51]. The beneficial effect of ivabradine on the processes of remodeling and systolic function of the LV was demonstrated in subisidiaries SHIFT [52]. 8-month therapy with ivabradine led to a significant decrease in end-systolic volume and LVEF. Took�, the values of LVEF> 5% and a reduction in CSR>15% was observed in ivabradine group and 1.5 times more frequent than in the placebo group. The influence of ivabradine on the performance of remodeling was less pronounced in patients with nonischemic etiology of heart failure.

In 2012, in an experimental study in vivo studies have shown that prophylactic administration of ivabradine before doxorubicin therapy prevents the development of cardiotoxic actions [53]. Therapy with doxorubicin resulted in increased heart rate, decreased activity of antioxidant systems: superoxide dismutase and catalase, increased levels of enzymes (LDH, MB-CPK), while treatment with ivabradine on the background of reduction of heart rate was restored the activity of antioxidant systems to the level of the control group and prevented the damage of cardiomyocytes.

Currently, in accordance with the database clinicaltrials.gov conducted more than 60 studies on the diagnosis and prevention of chemotherapy-induced cardiotoxicity. The bulk of research on prevention is carried out with blockers of the renin-angiotensin aldosterone system and beta-blockers. However, the decline of HELL can not use drugs of these groups at doses that have proven effective in cardiovascular diseases. Ivabradine - the first representative of the class of inhibitors of f-channels with�osobogo node, allows to selectively reduce heart rate, which is a risk factor for cardiovascular disease and mortality without additional reduce blood pressure.

Experimental studies show that ivabradine acts on the basic parts of anthracycline cardiotoxicity: the formation of reactive oxygen species, endothelial dysfunction and apoptosis of cardiomyocytes.

We previously summarized the existing experience of the use of ivabradine and outlined the main prospects of its use in kardiologii [prototype - 54]. At the same time, an elaborate use of ivabradine in a comprehensive scheme for the prevention of cardiotoxicity of chemotherapeutic agents were not previously available.

Our method allows to achieve the following results:

- to improve the systolic function of the left ventricle post-chemotherapy,

- to reduce the increased frequency of heart contractions per minute, thereby to reduce the risks of possible complications of the heart.

The proposed method is as follows.

Patients with confirmed diagnosis of breast cancer, which is recommended to undergo a course of chemotherapy, a week before treatment heart rate measurement is carried out according to electrocardiographic studies, performed after a five-minute rest.

�ri heart rate above or equal to 70 beats per minute is assigned to ivabradine in a daily dose of 10 mg. 4 weeks is repeated electrocardiographic study after a five-minute rest. At a heart rate above or equal to 70 beats per minute is carried out subsequent titration of the dose to 15 mg a day, and at a heart rate less than 70 beats per minute is maintained daily dosage of 10 mg.

When the initial heart rate less than 70 BPM in patients prescribed medication Trimetazidine in a daily dose of 70 mg for treatment all the time, regardless of future changes in heart rate.

All patients taking the drug for 6 months.

All patients before chemotherapy and during treatment is clinical and instrumental examinations: ECG, Echocardiography, clinical records is filled. Conducting Echocardiography performed using technology evaluation myocardial deformation. The study is carried out to chemotherapeutic treatment, 3 weeks after the first course, after 3 months, 6 months and 1 year after the start of treatment, thus assesses the effectiveness of the preventive action of ivabradine.

To confirm the effectiveness of the proposed method was investigated, which included 45 patients who were assigned to chemotherapy drugs anthracyclines, 14 - received ivabradine, 19 patients formed the control group, 12 were accepted Trimetazidine.

Results: In the background when�mA drug was significantly lower heart rate (p< 0.002) in the ivabradine group (Fig. 1).

In patients receiving the drug ejection fraction of the left ventricle remained unchanged (Fig. 2).

Identified the positive dynamics of indexes of global LV longitudinal strain, in comparison with the control group (Fig. 3, where No. 1 is the original, No. 2 - 3 months; P=0.05).

Figure 4 presents the dynamics of the global LV longitudinal strain in the ivabradine group (No. 1 - original, No. 2 - 3 months; P=0.002).

Clinical example 1

Woman 44 years, with confirmed diagnosis of breast cancer, which carried out radical surgery mastectomy on the left. The patient has 6 courses of chemotherapy according to the scheme CAF.

When collecting history is marked by the presence of peptic ulcer 12 duodenal ulcer, without exacerbation. At the time of inspection had no complaints.

On examination: no peripheral edema. Light - hard breathing, no wheezing, RR - 16 / min. Heart - tones are clear, no noise. PS=78 beats/min, rhythmic, BP=110/70 mm Hg.PT. The abdomen is not enlarged. Liver and spleen not palpable.

According to EchoCG AO - 2.5 cm, CANCER - 1.9 cm, LP - 0.0 cm, V = 33 ml, IVS 0.8 cm, CS - 0.7 cm, KDR - 4.2 cm, CEB - 2.4 cm, BWW 45 ml CSR 16 ml, EF - 64%.

The global longitudinal strain by 18.7%

The patient is assigned to ivabradine in a daily dose of 10 mg.

After 4 weeks in repeated ECG heart rate was 63 per min.

Daily dose of ivabradine the left�and at the level of 10 mg.

After 3 months in the control study:

peripheral edema no. Light - hard breathing, no wheezing, BH - 15 min. Heart - tones are clear, no noise. PS=56 beats/min, rhythmic, BP=120/80 mm Hg.PT. The abdomen is not enlarged. Liver and spleen not palpable.

According to EchoCG AO 2.4 cm, CANCER - 1.8 cm, LP - 3.5 cm, V = 35 ml, IVS 0.7 cm, CS - 0.7 cm, KDR - 4.6 cm, CEB - 2.4 cm, BWW 56 ml, CSR 19 ml, EF - 65%.

The global longitudinal strain of 20.4%

Thus, the positive dynamics according to the measure of global LV longitudinal strain, improves LV systolic function, despite the cardiotoxic effect.

Clinical example 2.

Woman of 49 years, with confirmed diagnosis of breast cancer, which carried out radical surgery mastectomy on the left. The patient has 6 courses of chemotherapy according to the scheme CAF.

During the history taking, the presence of chronic diseases denies. At the time of inspection had no complaints.

On examination: no peripheral edema. Lungs - vesicular breathing, wheezing no, BH - 14-in. Heart - tones are clear, no noise. PS=78 beats/min, rhythmic, BP=120/80 mm Hg.PT. The abdomen is not enlarged. Liver and spleen not palpable.

According to EchoCG AO - 2.7 cm, CANCER - 1.9 cm, PL - 0.6 cm, V = 37 ml, IVS 0.8 cm, CS - 0.9 cm, KDR - 5.0 cm, CEB - 2.5 cm, BWW 75 ml, CSR 32 ml, EF - 58%.

Results�whether global longitudinal strain - 17,2%

After 3 months in the control study:

peripheral edema no. Light - hard breathing, no wheezing, BH - 15 min. Heart - tones are clear, no noise. PS=87 beats/min, rhythmic, BP=120/80 mm Hg.PT. The abdomen is not enlarged. Liver and spleen not palpable.

According to EchoCG JSC 2.7 cm, CANCER - 1.9 cm, LP - 3.5 cm, V = 34 ml, IVS 0.8 cm, CS - 0.8 cm, KDR - 5.0 cm, CEB - 2.4 cm, KDO 66 ml, CSR 29 ml, EF - 57%.

The global longitudinal strain % - 14,6%

The dynamics of global longitudinal strain reflects the deterioration of LV systolic function, on the background of chemotherapy.

Clinical example 3

Woman of 49 years, with confirmed diagnosis of breast cancer, which carried out radical surgery mastectomy on the left. The patient has 6 courses of chemotherapy according to the scheme CAF.

When collecting history is marked by the presence of chronic diseases denies. At the time of inspection had no complaints.

On examination: no Peripheral edema. Light - hard breathing, no wheezing, BH - 15 min. Heart - tones are clear, no noise. PS=64 beats/min, rhythmic, BP=110/70 mm Hg.PT. The abdomen is not enlarged. Liver and spleen not palpable.

According to EchoCG AO 3.3 cm, CANCER - 2.2 cm, PL - 3.1 cm, V = 33 ml, IVS 0.8 cm, CS - 0.7 cm, KDR - 4.8 cm, CEB - 2.5 cm, BWW 96 ml, CSR 39 ml, EF - 58%.

The global longitudinal strain is 20.9%

Patient destinations�n Trimetazidine in a daily dose of 70 mg.

After 3 months in the control study:

peripheral edema no. Light - hard breathing, no wheezing, RR - 16 / min. Heart - tones are clear, no noise. PS=75 beats/min, rhythmic, BP=100/60 mmHg.PT. The abdomen is not enlarged. Liver and spleen not palpable.

According to EchoCG JSC 3.4 cm, CANCER - 2.2 cm, PL - 3.3 cm, V = 40 ml, IVS 0.8 cm, CS - 0.7 cm, KDR - 4.9 cm, CEB - 2.5 cm, MLC 103 ml, CSR 41 ml, EF - 61%.

The global longitudinal strain, % - 21.8% of

In this clinical example, the observed increase in global longitudinal strain C - 20.9 per cent to 21.8 per cent, amid drug Trimetazidine, pointing to the improvement in LV contractility, thus it is possible to conclude that the cardioprotective effect of Trimetazidine on the background of chemotherapy.

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52 Tardif J C et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011 Oct; 32 (20): 2507-15.

53 Colak M. C. et al. Therapeutic effects of ivabradine on hemodynamic parameters and cardiotoxicity induced by doxorubicin treatment in rat. Hum Exp Toxicol September 2012 vol. 31 no. 9 945-954.

54 A., Shkolnik, E. L., Netsvetov V. V., L. D. Student, Arlan G. V., A. V. sawyers Anthracycline cardiotoxicity: prospects for the use of ivabradine. Carismatica, 2012, Vol. 3, No. 4, pp. 65-69.

The method of prevention of anthracycline cardiotoxicity in patients with breast cancer involving the measurement of heart rate (HR) according to electrocardiographic studies performed since Fri�minute rest, moreover, the measurement is performed in the week prior to chemotherapy and at a heart rate above or equal to 70 beats per minute prescribed ivabradine in a daily dose of 10 mg and after 4 weeks, a second electrocardiographic study, after a five-minute rest, and while maintaining a heart rate above or equal to 70 beats per minute is carried out subsequent titration of the dose to 15 mg a day, and when reduction after 4 weeks heart rate less than 70 beats per minute keep the daily dosage of 10 mg, in that case, if the initial heart rate less than 70 beats per minute, prescribe Trimetazidine to a daily dose of 70 mg for treatment all the time, regardless of future changes in heart rate, these drugs are taken for 6 months.



 

Same patents:

FIELD: medicine.

SUBSTANCE: Holter ECG monitoring with recording total vegetative activity and measuring heart rate variability is conducted on the 21st day following ischemic stroke. Daily standard deviation of NN intervals (SDNN) is determined. If SDNN<71 ms, a high risk of cardiovascular complications following ischemic stroke is predicted.

EFFECT: method enables providing the informative and most accurate possible prediction of the risk of cardiovascular complications following ischemic stroke on the ground of daily standard deviation of NN intervals, which represent an independent predictive factor.

3 ex, 1 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: on the 21st day following an acute ischemic stroke, the patient has continuous Holter monitoring and ventricular extra systole recording. Observing frequent single ventricular extra systoles in number of more than ten an hour and grouped ventricular extra systoles enables predicting the high risk of cerebral complications following the ischemic stroke.

EFFECT: method enables predicting the high-grade risk of cerebral complications on the basis of ventricular extra systoles, which are an independent predictive factor of recurrent cerebral complications.

3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: estimation of the heart rate variability is realised by a method of 24-hour Holter monitoring of the 21st day from the moment of ischemic stroke development. After that, the power of a low-frequency spectrum is determined by means of spectral analysis and, if its value is lower than 117 ms2, a high risk of cardiac complications after the ischemic stroke is predicted.

EFFECT: method makes it possible to increase the accuracy of predicting a risk of development of cardiac complications after the ischemic stroke due to the identification of a certain LF value, an independent prognostic factor.

2 ex, 4 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: ECG is recorded. That is followed by a needle block of an ileocecal plexus with an anaesthetic solution in an amount of 60.0-80.0 ml; that is followed by recording another ECG after 60-90 min. The record is compared to the pre-block ECG record. If observing a positive dynamics in ECG results, ischemia caused by ileocecal-cardial inhibitory reflex is diagnosed, while no positive dynamics shows cardiogenic myocardial ischemia.

EFFECT: providing the more effective differential diagnostics of cardiogenic myocardial ischemia and ileocecal-cardial inhibitory reflex with underlying ileocecal patency.

1 ex

FIELD: medicine.

SUBSTANCE: heart rate variability is assessed. The assessment procedure involves 24-hour Holter monitoring on the 21st day from the moment of the ischemic stroke occurred. And if observing brady-arrhythmias presented by degree 2-3 atrio-ventricular block or degree 2-3 sinoatrial block and sinus pauses of more than 2 sec long, a high risk of cardiovascular fatal complications following the ischemic stroke is predicted.

EFFECT: method provides the high informative and flexible prediction of the risk of cardiovascular fatal complications following the ischemic stroke in the patients with cerebrovascular, cardiac, endocrine comorbidities.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: electric cardio signal recorder in free motion activity comprises an amplifier (1), an analogue-to-digital converter with a multiplex switch (2) and series decomposition unit (3), second arithmetical-logical unit (4), an arithmetic unit (5), an increment code analyser (6), a switchover unit (7) and a digital modem (8), as well as a control unit (9), first (12) and second (10) memory units, an increment code counter (11). A second output of the second arithmetical-logical unit (4) is connected to a first input of a decomposition unit (3); an output of the second memory unit (10) is connected to a second output of the second arithmetical-logical unit (4); a second output of the increment code analyser (6) is connected to a first input of the first memory unit (12), while a third output - to a first input of the increment code counter (11), an output of which is connected to a second input of the first memory unit (12) an output of which us connected to an second input of the switchover unit (7); first, second, third, fourth, fifth and sixth outputs of the control unit (9) are connected respectively to a first input of the analogue-to-digital converter with the multiplex switch (2), a second input of the decomposition unit (3), an input of the second memory unit (10), a third input of the second arithmetical-logical unit (4), a second input of the increment code counter (11) and a third input of the switchover unit (7). The device also comprises an electrode break detector (13) and a heart critical state detector (14). The amplifier (1), the electrode break detector (13), the analogue-to-digital converter with the multiplex switch (2), the heart critical state detector (14) and the decomposition unit (3) are series connected. A seventh output of the control unit (9) is connected to a fourth input of the switchover unit (7); a second output (17) of the electrode break detector (13) is connected to a first input of the control unit (9), a second input of which is connected to a second output (24) of the heart critical state detector (14), and a second output of the second memory unit (10) is connected to a second input (22) of the heart critical state detector (14).

EFFECT: using the invention enables enhancement by detecting the electrode break and the heart critical state in free motion activity.

3 cl, 12 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to paediatric cardiology and paediatric infectious diseases, and can be used for evaluation of indications for cardiometabolic therapy in case of infectious affection of myocardium in children. For this purpose quantitative evaluation of clinical, electrocardiographic, biochemical and echocardiographic indices is determined and realised. As clinical indices auscultative symptomatic: sonority of tones, presence of noises, parameters of arterial pressure are evaluated. As biochemical indices evaluated are: activity of cardiospeciphic enzymes: MB-fraction of creatine phosphokinase, α-hydroxybutyrate dehydrogenase, aspartic transaminase, alanine transaminase and cardiospecific troponin I protein. Echocardiographic examination is realised with application of Dopplerography for evaluation of diastolic ventricular function. Each of indices is evaluated by from 1 to 3 points. Points are summed up and obtained result is used to evaluate indications for cardiometabolic therapy. If the total sum is lower than 3 points, cardiometabolic therapy is not indicated. If the total sum is from 3 points to 7 point including, peroral introduction of cardiometabolic preparations is carried out. If the total sum is from 8 points and higher, parenteral introduction of cardiometabolic preparations is realised.

EFFECT: method provides possibility of determining presence of indications to administering cardiometabolic therapy objectively in minimal terms, including situations, when part of results of additional examination is absent because of some reasons, and of evaluating its efficiency in differential way.

1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to non-invasive techniques for qualitative-quantitative analysis of the cardiovascular functional state. A pulse signal and an electric heart signal are recorded for 2-3 minutes. The slow waves are recovered from two heart signals; slow-wave spectra are detected in two channels. The windowed Fourier transform is used to calculate spectral ratio powers of the slow waves of the heart signal in the second-order slow-term within the range of 0.01 to 0.05 Hz, in the first-order slow-term within the range of 0.05 to 0.15 Hz, in the respiratory component within the range of 0.15 to 0.5 Hz. The derived data are used to form six informative criteria X…X6. As the heart signal recorded in one of the channels, a heart rate is calculated and used as the seventh informative criterion. The generated seven-element vector of the informative criteria is supplied to an input of a trained neuron network, outputs of which correspond to the allocated classes of the cardiovascular diseases.

EFFECT: technique enables early diagnosing aiming at preventing the disease progression, thereby preventing an increase of the primary hypertension incidence by analysing two heart signals.

3 cl, 9 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: recording ECG is followed by a perianal block with an anaesthetic solution in an amount of 10.0-15.0 ml. Then 60-90 min later ECG is recorded once again, and this recording is compared to the pre-block recording. If observing a positive dynamics of the ECG results, ischemia caused by the anorectal cardioinhibitory reflex is diagnosed. No positive dynamics observed enables diagnosing cardiogenic myocardial ischemia.

EFFECT: method makes it possible to perform the more accurate differential diagnosis of the above pathologies by following a specific procedure in case of pain syndrome in the given category of patients.

1 ex

FIELD: medicine.

SUBSTANCE: recording ECG is followed by a bilateral translumbar block with an anaesthetic solution in an amount of 120-140 ml from each side. Then 60-90 min later ECG is recorded once again, and this recording is compared to the pre-block recording. If observing a positive dynamics of the ECG results, ischemia caused by the enteral cardioinhibitory reflex with underlying intraluminal intestinal hypertension is diagnosed. No positive dynamics observed enables diagnosing myocardial ischemia caused by a cardiac pathology.

EFFECT: enabling performing the more accurate differential diagnosis of the above pathologies by following a specific procedure in case of pain syndrome in the given category of patients.

1 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out pulsating Doppler echocardiographic examination. Mean pressure is determined in pulmonary artery. Mean pressure in pulmonary artery being less than 13 mm of mercury column, no cardiac rhythm disorders risk is considered to take place. The value being greater than 13 mm of mercury column, complex cardiac rhythm disorder occurrence risk is considered to be the case.

EFFECT: accelerated noninvasive method.

1 tbl

FIELD: medicine; medical engineering.

SUBSTANCE: method involves selecting reference point in every cardiac cycle on TP-segment. Values of neighboring N=2n+1 reference points also belonging to TP-segment are recorded, n=1,2,…, beginning from the first reference point. Other reference points are set to zero. The central reference point value is left without changes in a group of 2n+1 member. Reference point values of each of n pairs of reference points symmetrically arranged relative to the central reference point are scaled relative to condition Uj=U0Kj, where U0 is the central reference point amplitude, Uj is amplitude of j-th reference point pair, j=1,2,…,n is the number of each reference point pair relative to the central reference point, Kj is the scaling coefficients determined from received signal suppression condition of the first n spectral zones in spectrum. The so formed electrocardiogram signal reference point groups sequence is let pass through lower frequency filter with isoline drift signal being obtained being produced on output. The signal is amplified and subtracted from the initial electrocardiogram signal that is preliminarily delayed for lower frequency filter delay time. Device has the first lower frequency filter, discretization unit and unit for selecting anchor reference points connected in series, as well as subtraction unit, unit for saving N reference points, scaling unit, the second lower frequency filter, amplifier and delay unit. Output of the unit for selecting anchor reference points is connected to the first input of memory unit the second input of which is connected to discretization unit output. Each of N memory unit outputs is connected to one of N inputs of scaling units. Scaling unit output is connected to the second lower frequency filter input which output is connected to amplifier input. Amplifier output is connected to the first input of subtraction unit, the second output of subtraction unit is connected to delay unit output. Its input is connected to output of the first lower frequency filter. Subtraction unit output is the device output.

EFFECT: reliable removal of isoline drift.

2 cl, 8 dwg

FIELD: medicine; cardiology.

SUBSTANCE: device has amplifier, analog-to-digital converter provided with multiplexer, arithmetic unit, memory unit, digital modem, increment code analyzer, increment codes number counter, switching unit and control unit as well as second memory unit, digital filtration unit and decimation unit. Electrocardiogram signal is registered within frequency-time area. Increase in volume of diagnostic data is provided due to time localization of spectral components of electrocardiogram signal.

EFFECT: widened operational capabilities; improved precision of diagnosing; higher efficiency of treatment.

6 dwg

FIELD: medicine; radio electronics.

SUBSTANCE: device for taking cardiogram has set of electrodes, cardiologic unit, analog-to-digital converter, cardio signal preliminary treatment unit, computer, lower frequency filter, differentiator, functional converter and controlled filter. Power function calculation units are not included. Preliminary continuous filtering of cardio signal entering the computer is provided.

EFFECT: simplified design; improved precision of measurement.

1 dwg

FIELD: medical engineering.

SUBSTANCE: device has electrodes, input amplifier, unit for protecting against error influence when applying medical electric instruments, low frequency filter, signal analysis unit, unit for eliminating isoline drift and electric power supply units.

EFFECT: high accuracy in plotting rhythmograms; improved instruments manipulation safety.

1 dwg

FIELD: medicine.

SUBSTANCE: method involves modeling real three-dimensional patient heart image based on electrocardiogram and photoroentgenogram data and determining basic functional values of its myohemodynamics.

EFFECT: high accuracy and reliability of the method.

2 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves recording cardiac biopotentials with vector electrocardiograph, processing and visualizing signal with graphical plane integral cardiac electric vector projections (vector electrocardiograms) being built and analyzed. Shape, QRS-loop value and vector orientation-recording process are determined. Analysis is based on planar vector electrocardiograms in horizontal, frontal and sagittal planes and in spatial 3-D-form. Vector loop direction is studied in X-,Y-,Z-axis projections, values, dynamics and localization are evaluated in resulting integral cardiac electric vector delta-vector space. To do it, QRS-loop is divided into four segments, one of which characterizes excitation in middle part of axial partition surface, the second one is related to excitation in lower ventricular septum one-third with cardiac apex being involved and the third and the fourth one is related to excitation in basal parts of the left and right heart ventricles. Delta-vector existence and its magnitude are determined from changes in loop segment localization when compared to reference values.

EFFECT: improved data quality usable in planning surgical treatment.

4 dwg

FIELD: medical radio electronics.

SUBSTANCE: device can be used for testing cardio-vascular system of patient. Differential vector-cardiograph has high frequency oscillator, common electrode, unit for reading electrocardiogram and radio cardiogram provided with amplification channels and filtration channels, multiplexer, microprocessor unit with common bus, analog-to-digital converter, keyboard, mouse and indication unit. Device provides higher precision of measurements due to usage of electric component heart activity and truth of diagnostics due to ability of representation of results of testing in form of variety of vector-cardiograms in real time-scale.

EFFECT: improved precision.

1 dwg

FIELD: medicine, cardiology, arhythmology, functional diagnostics.

SUBSTANCE: one should register electrocardiogram in esophagus, apply an electrode in a site where the maximum signal amplitude is registered, increase the signal 5-fold, not less to be filtered in the range of 0.5-40 Hz to be registered at the rate of 100 mm/sec, not less. The time for intra-atrial process should be measured from the beginning of ascending part of the first positive wave of pre-P-tooth up to the top of the second adhesion of P-tooth; the time for inter-atrial process should be measured from the site of crossing a descending part of the first positive wave and the onset of obliquely ascending pre-P-interval up to crossing this interval with the point of abrupt increase of the first phase of P-tooth. The innovation provides more means for noninvasive evaluation of intra- and inter-atrial stimulation process.

EFFECT: higher accuracy of evaluation.

3 dwg

FIELD: medicine, cardiology.

SUBSTANCE: one should register a standard electrocardiogram (ECG) and measure the duration of a "P"-wave. Moreover, it is necessary to conduct daily ECG monitoring to calculate single, paired and group atrial extrasystoles. Then one should calculate diagnostic coefficient DC by the following formula: DC=DC1+DC2+DC3+DC4, DC1 =-8.8 at duration of "P"-wave below 106 msec, 9.3 at duration of "P"-wave above 116 msec, -3.5 at duration of "P"-wave ranged 106-116 msec. DC2=-1.9 at the absence of group atrial extrasystoles during a day, 8.3 -at daily quantity of group atrial extrasystoles being above 4, 2.5 - at daily quantity of group atrial extrasystoles ranged 1-4. DC3=-2.9 at daily quantity of paired atrial extrasystoles being below 3, 8.1 - at daily quantity of paired extrasystoles being above 35, -1.4 - at daily quantity of paired atrial extrasystoles ranged 3-35. DC4=-5.1 at daily quantity of single atrial extrasystoles being below 15, 4.3 - at daily quantity of single atrial extrasystoles being above 150, -1.0 - at daily quantity of single atrial extrasystoles ranged 15-150, if DC is above or equal to 13 one should diagnose high risk for the development of paroxysmal atrial fibrillation, in case if DC is below or equal -13 it is possible to diagnose no risk for the development of paroxysmal atrial fibrillation, and if DC is above -13 and below 13 - the diagnosis is not established.

EFFECT: higher sensitivity of diagnostics.

5 ex

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