Abstract of Vladimir A. Pavlov's Dissertation for the Degree of Candidate of Medical Science

FOURTH MAIN DEPARTMENT OF MINISTRY OF HEALTH OF THE USSR
CENTRAL RESEARCH LABORATORY
Printed as manuscript

Vladimir A. PAVLOV
UDK 616.127-005.8-089.584-036.I

INFLUENCE OF TRANSCRANIAL ELECTROSTIMULATION ONTO OPIATE SYSTEMS AND MYOCARDIAL INFARCTION COURSE



/14.00.06 – Cardiology/

Abstract of
Dissertation for the Degree of
Candidate of Medical Science

Moscow – 1989


The study has been carried out at the Moscow Emergency Research Institute of Order of Lenin and Red Banner of Labour named after N. V. Sklifosovsky.

Head of research:
Doctor of Medical Science, Professor, Associate Member of Academy of Medical Sciences, A. P. GOLIKOV
Official Opponents:
Doctor of Medical Science, Professor, V. I. MAKOLKIN
Doctor of Medical Science, Professor, A. S. MELENTYEV

Lead agency:
Moscow Dental Institute of Red Banner of Labour named after N. A. Semashko

The defense of the dissertation will take place on November, 20, 1898, at 14:00 at the meeting of the Specialized Council K.074.43.01 in the Central Research Laboratory of the Fourth Main Department of the Ministry of Health of the USSR.

Address: 6, Kalinina prospect, 103875, Moscow.

The Abstract of Dissertation is possible to get acquainted with at the library of the Fourth Main Department of the Ministry of Health of the USSR.

The Abstract of Dissertation was distributed on October, 20, 1989.

Academic Secretary of the Specialized Council of the Central Research Laboratory of the Fourth Main Department of the Ministry of Health of the USSR, Doctor of Medical Science, N. K. ROZOVA
Urgency of an issue: The modern pathogenic therapy of myocardial infarction is based on the concept of the interrelationship between the sizes of myocardium necrotic affection, the process of granulation tissue maturation in the infarcated areas, the development of compensatory metastructure hyperplasia in the non-infarction heart cardiomyocites and the clinical severity (P. E. Lukomsky, 1957; E. I. Chazov, 1973, 1977; A. P. Golikov and co-authors, 1983, 1986; G. G. Avtandilov and co-authors, 1984; A. Tarankin and co-authors, 1984; J. Herilits and co-authors, 1984).
The main directions of myocardial infarction treatment are: the localization of the necrosis (N. G. Babkar, 1983; V. Yu. Polumiskov, 1983; A P. Golikov, 1986; J. A. Cairus, 1981), the acceleration of the necrotic cell mass dispersion and cicatrisation, the stimulation of the regenerative processes in the circum-infarcated areas by means of intracellular reparative regeneration mobilization, and the stimulation of the buildup of the compensatory hypertrophy of the remaining myocardium (D. S. Sarkisov, 1973; E. I. Sharov and co-authors, 1984; L. I. Aruin and co-authors, 1987; D. R. Alonso and co-authors, 1973).
At the present day the scientists pay close attention to neuropeptides that form the system regulating the metabolic and physiologic processes and protect the body against the adverse effect of external factors (G. Ya. Balakin and co-authors, 1981; E. I. Chazov and co-authors, 1984; G. W. Tregear, 1981). The neuropeptides include the opiate peptides inter alia – in particular, the enkephalins and endorphines regulating various functions of central nervous system and being able to influence the targeted cells directly (E. I. Chazov, 1981; E. I. Chazov and co-authors, 1984).
Not long ago there were published the first data based on the results of the introduction of the opiate peptide synthetic analogue (dalargin) to animals with an experimentally induced myocardial infarction. These results showed that the end size of the necrotic area diminished under the medication effect (V. S. Pavlenko and co-authors, 1986; V. D. Slepushkin and co-authors, 1986) and the reparative processes gather pace (N. I. Afonskaya and co-authors, 1986).
At the same time the number of authors showed that the increase of the opiate peptides circulating in the body can be reached not only by their exogenous introduction, but by the endogenous opiate systems mobilization with the help of transcranial electrostimulation inducing the opiate peptides intense ejection into blood and neurolymph (Ya. S. Katznelson and co-authors, 1983; L. N. Ayrapetov and co-authors, 1985$ V. P. Lebedev, 1986).
All this gave the grounds for the including into myocardial infarction complex therapy of the transcranial electrostimulation that had never been used earlier for this purpose.
The aim of the present research was to study the transcranial electrostimulation influence onto myocardial infarction course.
Considering the research aim, the tasks were as follows:
to study the transcranial electrostimulation influence onto necrosis locus;
to estimate the transcranial electrostimulation effect onto reparative processes;
to estimate the transcranial electrostimulation action considering the characteristics of central hemodynamics and left ventricle contractile and transport function;
to estimate the transcranial electrostimulation influence onto beta-endorphin concentration in the blood plasma;
to study the change of the characteristics of heart contractile and transport function, peripheral hemodynamics, external respiration, ventilation and lipid peroxidation after the single transcranial electrostimulation run;
to estimate the transcranial electrostimulation treatment influence onto myocardial infarction clinical course.
Research academic novelty: It was the first time when the transcranial electrostimulation method was applied to the myocardial infarction complex therapy and its influence onto the disease course was studied.
Academic provisions to be defended:
Against the background of the daily application of the transcranial electrostimulation during the first 15 days of the myocardial infarction, there is an acceleration of the reparative processes, in particular, of the postinfarction cicatrix buildup, the development the compensatory hypertrophy of the intact myocardium section, and the amelioration of left ventricle contractile and transport function.
One of the transcranial electrostimulation action mechanisms is the increase of the beta-endorphin level in blood.
After the run of the transcranial electrostimulation there is a rise of the initially degraded heart contractile and transport functioning, an increase of the peripheral blood-flow and a reduction of the vascular resistance, a decrease of  the arterial hypoxemia intensity caused by the ventilation amelioration, a reduction of the lipid peroxidation products in blood.
The transcranial electrostimulation therapy applied to the myocardial infarction cases smoothes the disease clinical course resulting in the decrease of the anginal diseases relapse number, of the myocardial infarction prolonged course and of the congestive heart failure occurrence.
Research practical value: The received data enable us to recommend the transcranial electrostimulation method to be used free as part of the myocardial infarction cases therapy for the purpose of the reparative processes acceleration, the amendment of heart contractile and transport functioning and the disease clinical course relief.
Research results implementation: The transcranial electrostimulation was introduced as the method of myocardial infarction therapy into the practice of the cardiac intensive care department of the Moscow Emergency Research Institute named after N. V. Sklifosovsky and the cardiac intensive care department of the hospital of the Academy of Sciences of the USSR.
Dissertation confirmation:
The general provisions of the dissertation were reported:
at the city conference of young scientists considering the issue “Emergency Cardiology” (Moscow, 1988);
at the city research and practice conference considering the issue “Myocardial infarction” (Moscow, 1988).
Publications:
There were published 4 printings under the materials of the research.
Dissertation volume and structure:
The dissertation is laid out in 105 typescript pages and consists of the introduction, 4 chapters (the literature review, the research materials and methods, the results of the research, the discussion of the received results), the conclusion and practical recommendations. The work is illustrated with 10 tables and 6 figures. The list of literature contains 86 works of the national authors and 127 – of the foreign ones.

DISSERTATION CONTENTS

Research materials and methods: We examined 80 macrofocal myocardial infarction patients admitted to the cardiac-emergency department of the Emergency Cardiology Centre of Moscow city (on the basis of the Moscow Emergency Research Institute named after N. V. Sklifosovsky) up to 12 hours after the disease emergence. Using the random sample method, the patients were divided into 3 groups. The first (control) group included 40 cases (34 male and 6 female with an average age of 54.5±1.8 years) after their entry receiving the polarizing solution and, at a later stage, the accepted complex comfort therapy. The second group consisted of 11 cases (7 male and 4 female with an average age of 58.4±1.4 years) undergoing a single run of the transcranial electrostimulation. The third group contained of 29 cases (26 male and 3 female with an average age of 55.7±1.4 years) after their entry undergoing the transcranial electrostimulation therapy (one run per day for 15 days) together with the therapy, being received by the first group. The represented group of the myocardial infarction patients undergoing the long-term transcranial electrostimulation therapy and the control group were comparable considering their clinical data, which enables us to carry out their comparative assessment.
We estimated the size of the necrotic affection of the myocardial infarction patients using biochemical and electrophysiological methods. The total creatine phosphokinase activity level was measured with the Labsystems FP-9 reaction rate analyzer (Finland) by the kinetic method of T. Olivier-S. B. Rosalski considering its G. Szasr modification; the kinetic curves were calculated on the Hewlett Packard HP-9815A computer (USA) using standard programmes. The activity level of the creatine phosphokinase myocardial fraction was measured by the immunoinhibition method using the Boehringer sets (Federal Republic of Germany). The blood sampling was carried out every 3 hours till 18:00, and then every 6 hours till the end of the 2nd day, and then 60.72 and 96 hours after the myocardial infarction emergence. We also performed the electrocardiac topography recording considering 35 precordial chest leads by the procedure of P. R. Maroko and co-authors (1972) with the modifications of A. V. Vinogradov and co-authors (1982). The received data were recorded with Siemens Mingograf-4 appliance (Federal Republic of Germany) on the patient’s entry, 0.5 hour after the transcranial electrostimulation run, and then on the 2nd, 3rd, 5th, 10th, and 25th day after the myocardial infarction emergence.
To assess the reparative processes run we used the time course of protein-bound hydroxyl-proline concentrations in blood plasma, micromole/l (of metabolite collagen reflecting the collagen production in the body), defined by the chromatographic method of I. Bergman and R. Loxley (1963), modification of A. A. Krel and L. N. Furtzeva (1968). The blood samples were taken on the patient’s entry, and then on the 5th, 10th, 15th, 20th and 25th day after the myocardial infarction emergence. We estimate the compensatory hypertrophy buildup considering the dynamics of the aggregate waves peak value (R) of the precordial electrocardiac topogram (Σ Rh, mm).
The beta-endorphin concentration in the blood plasma of the myocardial infarction patients was defined on the moment of their entry to the in-patient clinic, before and after the transcranial electrostimulation run, and on the 2nd, 3rd, and 5th day after the myocardial infarction emergence by the radioimmunochemical method using the Immuno Nuclear Corp. assay kit (USA) and the L KV gamma- counter (Sweden).
To define the patients’ central hemodynamics characteristics we applied the integral rheography method of M. I. Tischenko and co-authors (1973), modification of V. A. Estrin (1980), using the RPG 2-02 impedance plethysmograph. The heart contractile and transport function was assessed on the basis of phase analysis method. The characteristic values were recorded with the same equipment and intervals as the precordial electrocardiac topograms.
The patients’ external respiration and ventilation function parameters were examined with the BOC Right respiration monitor (England) and the Gordon analyzers of carbon dioxide and oxygen level in the inspiratory air (Holland). The gas composition of the arterial and mixed venous blood was estimated by the micro-Astrup method with the Radiometer ABL-2 appliance (Denmark). The tests were carried out before and after the transcranial electrostimulation run.
The right ventricle respiration and ventilation function (dP/dt % mmhg) was estimated considering the venous heart catheterization. The data were recorded with the Siemens Mingograf-803 (Federal Republic of Germany) before and after the transcranial electrostimulation run.
We also studied the peripheral circulation by the occlusive plethysmography with the Gutman Piriquant-3500 device (Federal Republic of Germany) before and after the transcranial electrostimulation run.
The received examination results were processed by methods of medical and biological variance analysis and are represented as M±m. The credibility of the averages discrepancy in the studied groups was defined using the Student criterion.

The results of the research and their discussion:
According to the data of the electrocardiac topography on the back of the transcranial electrostimulation therapy, the dynamics of the ischemic damage differed from the one in the control group. Considering the ΣST values up to the 5th day of the myocardial infarction we found no certain difference, but on the 10th and 25th days of the disease this index was to be reliably lower than that one in the control group (Table 1). Considering the necrotic areas up to the 10th day of the myocardial infarction there was no certain difference either. In the moment of the lesion build-up (on the 2nd day of the myocardial infarction) defined according to the dynamics of the aggregate square of the pathologic peaks and complexes QS (ΣSQ + ΣSQS) and the necrotic affection calculated mass (m), the results were practically the same in both groups.

When carrying out series assessment of the total creatine phosphokinase and phosphokinase myocardial fraction activity level in the blood, we found no certain difference between the groups of the patients up to the end of the 2nd day, which is also proved by the characteristic values of the precordial electrocardiac topography.
Nevertheless, the changes in value of the characteristics of the necrotic area and viable myocardium mass in the subacute period against the transcranial electrostimulation treatment differed much of the ones in the control group.
On the 25th day of the myocardial infarction the value of the necrotic affection (ΣSQ + ΣSQS) tended to decrease totaling 22.8% which is relatively less than that in the control group (Table 1). On the other hand, the m value of the patients undergoing the transcranial electrostimulation therapy on the 25th day of the infarction started becoming less than that of the control group (Table 1).
The value of the remaining viable myocardium (ΣRh) is similar in both groups up to the 3rd day of the infarction. Nevertheless, at a later stage, as of the 5th day, there appeared a certain increase of ΣRh in the group of the patients undergoing transcranial electrostimulation therapy, showing a certain difference with the control group (Table 1). This increase of ΣRh indicates the rise in mass of the viable myocardium (A. Richter and co-authors, 1987; V. A. Karev, 1987) that means the accelerated development of the compensatory myocardium hypertrophy of the non-infarction heart.
The initial protein-bound hydroxyl-proline concentrations in both groups corresponded to that one of the healthy. In the following the control group showed the decrease of the protein-bound hydroxyl-proline concentrations indicating the collagen metabolism oppression. On the contrary, the patients’ transcranial electrostimulation therapy resulted in the rise of the blood concentration of the protein-bound hydroxyl-proline reaching reliable values on the 5th, 10th and 15th days in comparison with the control group (Table 2), which is the indication of the collagen metabolism activation (V. A. Karev and co-authors, 1987).

Therefore, against the transcranial electrostimulation therapy, the myocardial infarction patients’ reparative processes speed up resulting in the acceleration of the postinfarction cicatrix buildup and development of the compensatory hypertrophy of the non-infarction myocardium section.
One of the mechanisms of the transcranial electrostimulation influence onto the reparative processes course considering myocardial infarction is the increase of the beta-endorphin circulating in the blood plasma (Figure 1). As usual, after every transcranial electrostimulation run there was registered a certain double rise in the beta-endorphin concentration in the blood plasma. Despite of the therapy discontinuity (the transcranial electrostimulation runs were carried out only once a day), there was determined the increase of the basal beta-endorphin concentration in blood: on the 3rd day of the myocardial infarction before the run beta-endorphin concentration in blood reliably exceeds that one of the control group.
According to E. I. Chazov and his co-authors (1984), it is advantageous to use neuropeptides by intermittent injections and in optimal doses. The effect can be preserved for a long period of time even after the single increase of the peptides due to their absorption by the target cells exposing a certain influence onto the cell genome expression.
During the course of treatment of the myocardial infarction patients there was indicated the decrease of the expressed arterial hypoxemia which also supports the postinfarction cicatrix buildup.
There are also some positive results of the transcranial electrostimulation therapy study considering the stimulation influence onto the peripheral hemodynamics and heart contractile and transport function of the myocardial infarction patients. It is established that the introduction of the transcranial electrostimulation into the complex therapy improves the peripheral blood-flow.


Thus, for example, against the transcranial electrostimulation run, the blood-flow volume increased in average from 0.96±0.18 to 2.84±0.66 mm per 100 mg of the tissue. There was also observed a certain rise in the initially depressed ventricles contractile and transport function (for the left one: from 67.9±6.6 to 99.7±8.6 % to the due value; for the right one: from 511±48 to 730±37 mm hg) while the normal values remained as they were.
The mechanisms of the transcranial electrostimulation influence onto hemodynamics characteristics are mediated due to the central and peripheral effects of the opiate peptides, in particular, of the beta-endorphin (W. De Jony and co-authors, 1983; D. W. End and co-authors, 1981; G. L. Stiles and co-authors, 1981). Under the conditions of the pathologically changed functions of the cardiovascular system, the opiate peptides exert their positive effect not only through the central and peripheral nervous system, but through the direct influence onto the myocardium function as well (J. L. Caffrey and coauthors, 1985; T. M. Wong and co-authors, 1985).
A matter of special interest is the transcranial electrostimulation influence onto the ventilation. There was determined that the transcranial electrostimulation has a definite membrane-protective effect enhancing the alveoloarterial membrane permeability (the alveoloarterial CO2 gradient was decreasing from 4.03±0.72 to 0.80±0.75 mm hg on average against a transcranial electrostimulation run). This turned out to be one of the mechanisms diminishing the arterial hypoxemia due to the effect of the electrical stimulation of the opiate systems (the partial O2 intensity in the arterial blood increased from 63.8±1.9 to 72.8±2.8 mm hg). The transcranial electrostimulation antioxidative effect is also significant here (Z. Varlikyavichene, 1983; N. V. Syromyatnikova and co-authors, 1987).
The melioration of the myocardial infarction clinical course against the transcranial electrostimulation therapy rises first from the myocardium reparative processes acceleration and heart contractile and transport functioning improvement. As a result, the cardiac failure symptoms that the patients have on the entry promptly disappear and the new patients contract the cardiac failure phenomenon much more seldom that the ones of the Control Group. That means that the transcranial electrostimulation exercise a curative and proactive effect onto the cardiac failure.
The decrease of the number of cases of the anginal diseases relapse and myocardial infarction prolongation due to the effect of the transcranial electrostimulation is strongly related to the antioxidative and antihypoxic action of opiate peptides (V. Adomenis and co-authors, 1981; T. M. Wong and co-authors, 1985). Thus, in the main group there were only 3 cases of the illness prolonged course (10.3%), while the Control Group got the entire 12 cases (30%).
It was found out that the number of postinfarction cardiac aneurysm occurs much more rarely against the transcranial electrostimulation therapy as well. This subsequent disease was detected in 44.8% cases among the transcranial electrostimulation group patients and in 62.5% cases among the ones of the Control Group though the necrotic affection size and locus were the same for both groups.
This transcranial electrostimulation effect first of all results from the accelerated maturation of the granulation tissue in the infarcated areas and rapid build-up of the full-featured connective tissue cicatrix hardening the cardiac wall in the necrotic area and averting the systolic heave development and the following cardiac aneurysm forming (V. A. Vinogradov and co-authors, 1983; G. G. Avtandilov and co-authors, 1984).
Much of the transcranial electrostimulation positive effect considering the frequency and intensity of the cardiac failure is owned to the accelerated course of the reparative processes and the resulting rapid recovery of the heart contractile and transport function. Thus, for example, 41% of the Control Group patients experienced cardiac failure on the 4th-5th myocardial infarction day in comparison with 11,1% of the patients undergoing the electrostimulation.
The rhythm disturbance was also diagnosed less frequently against the transcranial electrostimulation. For example, the ventricular and auricular arrhythmia was registered on the 3rd day among 20.5% of the Control Group patients in comparison with 7.4% of the main group patients.
The case fatality rate in the Control Group totaled 17.5% (12.5% - cardiac rapture; 5% - progressive cardiac failure). Against the transcranial electrostimulation the case fatality rate amounted to 10.3% and there were no progressive cardiac failures (all the patients died of cardiac rapture).
Generally, the wide range of the transcranial electrostimulation positive effects onto the reparative processes, central and peripheral hemodynamics, heart contractile and transport function, ventilation and myocardial infarction clinical course, as well as the absence of by-effects and the reduction of the financial costs make the wide use of this method within the myocardial infarction complex therapy efficient and advisable.

CONCLUSION

1. The introduction of the transcranial electrostimulation into the myocardial infarction complex therapy has a positive effect onto the disease clinical course reducing the number of cases of: anginal diseases relapse, myocardial infarction prolongation, rhythm disturbance, cardiac aneurysm forming, and cardiac failure occurrence.
2. Considering the myocardial infarction patients, the transcranial electrostimulation of the opiate systems enhance the acceleration of the reparative processes (in particular, of the buildup of postinfarction cicatrix and the development of the compensatory hypertrophy of the intact myocardium section).
3. Against the myocardial infarction patients’ treatment with the opiate systems transcranial electrostimulation there is detected the improvement of the heart propulsive and contractile function, as well as of the peripheral blood-flow.
4. The transcranial electrostimulation of the opiate systems improves the ventilation and brings down the activation of the lipid peroxidation resulting in the reduction of the patients’ arterial hypoxemia intensity.
5. The use of the transcranial electrostimulation of the opiate systems does not limit the size necrotic affection areas of the myocardial infarction patients.
6. One of the basic mechanisms of the transcranial electrostimulation influence onto the myocardial infarction course is the endogenous opiate systems mobilization followed by the increase of the beta-endorphin concentration in the blood plasma.

PRACTICAL RECOMMENDATIONS

In order to encourage the reparative processes, the amelioration of the central and peripheral hemodynamics, heart contractile and transport function and myocardial infarction clinical course, it is recommended to use the transcranial electrostimulation of the opiate systems per diem, starting as of the first day of the disease and carrying out one run lasting 30-40 minutes, the whole therapy course totaling 15 runs.
In practice the method should be realized as follows: attach the electrodes with hydrophilic laying onto the supraorbital area of the patient’s frons and his/her mastoid bones and fix them. Energize these electrodes with direct current fading in for 1-2 minutes up to 3.3-6.8 mA (depending on the individual acceptability). Then energize the same electrodes with rectangular impulses of the same polarity, a frequency of 70-80 Hz and duration of 3-4 ms, increasing their amplitude for 1-2 minutes up to 1.7-3.4 mA corresponding to the direct current in the ratio of 2:1.
The absence of by-effects, the method availability and simplicity, as well as its enhancing the reduction of the financial costs, enable us to recommend the transcranial electrostimulation of the opiate systems for the wide use within the therapy of the myocardial infarction cases.
List of Publications covering Dissertation Subject

1. Application for an invention as of 21.07.87. - Registration number 4288225/28-14/121518. - Way of Treatment of Acute Myocardial Infarction Cases by Transcranial Electrostimulation of Opiate Systems. – In collaboration with A. P. Golikov, O. B. Ilyinsky, V. A. Ryabinin, V. Yu. Polumiskov, V. A. Karev, A. K. Trofimov, V. P. Lebedev, Ya. S. Kaznelson. – The positive decision of the Committee of All-Russian Research Institute of State Patent Examination on 23.01.88: “To recognize the claim and issue the certificate of authorship”.
2. First Experience of Transcranial Electrostimulation Use regarding Myocardial Infarction Patients.// Actual Issues of Diagnostics and Treatment in Emergence Cardiology. The republic collection of scientific papers. – Moscow, 1988. – Pages 68-72.
3. Possibilities of Non-medicated Correction of Beta-endorphin Level in Blood of Patients with Myocardium Infarction.// Myocardium Infarction Treatment. The republic collection of scientific papers. – Moscow, 1989. – Pages 71-76. – (Co-authors: V. A. Karev, V. P. Lebedev, Ya. S. Kaznelson).
4. Influence of Transcranial Electrostimulation of Opiate Systems onto Post-infarction Period Course.// Myocardium Infarction Treatment. The republic collection of scientific papers. – Moscow, 1989. – Pages 76-80.