Study of Electrophysiological Properties of Atrioventricular Node in Permanent Cardiac Pacing under Influence of Trimetazidine Dihydrochloride

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LIST OF ABBREVIATIONS

AV — atrioventricular

CA — cardiac arrhythmias

CHD — coronary heart disease

CHF — chronic heart failure

CP — cardiac pacing

EPE — electrophysiological examination

IVS — interventricular septum

LV — left ventricle

PICS — postinfarction cardiosclerosis

SSS — sick sinus syndrome

WPA — Wenckebach point, antegrade

INTRODUCTION

Among numerous cardiac arrhythmias (CA), of special importance cardiac pacing methods had been introduced in clinical practice, the annual mortality rate of patients with acquired complete atrioventricular block exceeded 50% [2, 3]. In chronic bradycardias/conduction disorders, pharmacological antiarrhythmic drugs are in most cases ineffective — a gold standard of treatment is permanent electrical pacing [4–6].

The number of antiarrhythmic devices implanted in the Russian Federation, annually increases by 10% [7], and currently reaches about 50 thousand devices [8]. The majority of devices are dual-chamber pacemakers (in Europe — 60%–70%) [9]. This type of stimulation permits to maintain electrophysiological atrioventricular synchronization: the impulse travels from atria to ventricles along the natural pathway with delay analogous to propagation of excitation through the atrioventricular node (AVN) of a healthy individual. Abnormal activation of ventricles in stimulation of the right ventricle, like in the left bundle branch block, leads to impairment of the function of the left ventricle (LV) and its structural alterations resulting from the electrical and mechanical dyssynchrony of the myocardium [10]. The basis of stimulation of the right ventricle is the reduction of increase in systolic thickening of the interventricular septum (IVS) and increase in diastolic pressure in the cavity of the LV. During contraction of the LV, the mechanical work of IVS may decrease with increase in the load in the area of the free wall of the LV, which leads to its hypertrophy [11].

In patients with ventricular pacing exceeding 50%, the frequency of the recorded cases of heart failure and deaths over a 4^th year follow-up period was 25% higher than in the group with ventricular stimulation below 50% [11]. Therefore, the delay interval must be formed in the way to reduce the percent of the right ventricular stimulation. This preserves the LV ejection fraction, decreases the risk of development of chronic heart failure (CHF), increases the functional abilities of the patient and decreases the risk of atrial fibrillation. On the other hand, increase in the AV delay above the limit leads to pacemaker syndrome: impairment of the function of circulation, shortness of breath, poor tolerance to exercise, dizziness, syncopal conditions.

Many patients to whom a pacemaker is implanted are already having comorbid pathologies: coronary heart disease, (CHD), CHF, arrhythmias. These diseases require intake of drugs that also worsen the AV conduction (β-blockers, antiarrhythmic drugs, etc.).

The question of the influence of the permanent electrical pacing on the antegrade AV conduction remains unsolved.

The aim to this study the effect of trimetazidine dihydrochloride on the antegrade atrioventricular conduction in patients with different heart rhythm disorders and disorders in conduction in the permanent electrical pacing in different modes, to study the effect of electrical pacing on the activity of the atrioventricular node in 6-month follow-up period.

MATERIALS AND METHODS

The study included 86 patients with bradysystolic forms of arrhythmia who were implanted permanent pacemaker systems in conditions of Yaroslavl Regional Clinical Hospital in the period from 2019 to 2021. The research protocol was approved by the Local Ethics Committee of the Yaroslavl State Medical University (protokol No. 41 dated October 22, 2020). The signing of the Informed Consent was carried out according to standard procedures of the Yaroslavl Regional Clinical Hospital before performing any medical interventions.

Inclusion criteria:

– age 18 years and older;

– the main disease: sick sinus syndrome (SSS) or II or III degree AV block;

– first implantation of a dual-chamber pacemaker;

– implantation of the right ventricular electrode only into the interventricular septum;

– implantation of the right atrial electrode only into the auricle of the right atrium;

– sinus rhythm recorded at all stages of the study;

– absence of evident cardiac defects and interventions on the open heart in history;

– adherence of patients to the adequate drug therapy;

– the expected follow-up period of 6 months and more.

In result, the study included 28 (32.6%) men and 58 (67.4%) women aged 32 to 94 years, the mean age 74.26 ± 11.47 years. The studied patients had different forms of SSS (38 patients, 38%) and of AV blocks (permanent I degree AV block — 11 patients (11%), transient II degree AV block — 14 patients (14%), permanent III degree AV block — 23 patients (23%)). Most patients had comorbid diseases: essential hypertension — 81 patients (94.2%) (III stage — 80 patients (99.3%), II stage — 1 patient (1.2%)); I stage CHF (by Strazhesko–Vasilenko classification) — 4 patients (4.7%), IIA stage — 46 patients (53.5%), IIB stage — 8 patients (9.3%); CHD — 51 patients (59.3%) including postinfarction cardiosclerosis (PICS) — 17 patients (19.8%); diabetes mellitus — 26 patients (30.2%); nodular goiter — 11 patients (12.8%); chronic kidney disease of different extent of severity — 11 patients (12.8%); chronic cerebrovascular insufficiency with preceding acute cerebrovascular event — 2 patients (2.3%); aortic stenosis — 2 patients (2.3%); mitral insufficiency — 1 patient (1.2%), combined mitral-aortic stenosis — 1 patient (1.2%).

The following groups of patients were formed:

group 1 — patients with SSS (n = 38, 44.2%);

group 2 — patients with II degree AV block (n = 25, 29.1%);

group 3 — patients with III degree AV block (n = 23, 26.7%).

By the basic clinical and demographic data (mean age and the number of comorbid diseases), except for the gender of the patients, the groups were comparable (Table 1), which enabled further comparative analysis of the results of the study. Gender differences between the groups were neglected due to the absence of any mention of the effect of gender of healthy individuals on the activity of the AV node in the literature.

Table 1. Clinical and Demographic Characteristics of Study Groups of Patients

All the patients underwent surgical treatment — implantation of a permanent electrical pacemaker (EP). Dual-chamber pacemakers were used with passive and active electrodes with the “atrial” electrode placed in the auricle of the right atrium and the “ventricular” electrode of the right ventricle placed in the area of the middle third of IVS. The operations were performed under local anesthesia in the x-ray operating room. Also, all the patients were administered the drug under study — trimetazidine dihydrochloride — at a dose 80 mg orally once a day in the morning.

Electrophysiological properties of the conducting system of the heart and the activity of the AV node were evaluated by determination of Wenckebach point antegrade (WPA) intraoperatively (in testing the EP system), in 24–48 hours after EP implantation, in 6–8 hours after intake of trimetazidine dihydrochloride, in 7, 14, 9 and 180 days after intake of trimetazidine dihydrochloride and in 7, 14, 21 and 30 days after its cancellation (to evaluate the extent of antegrade AV node conduction, it was required in testing to set EP to AAI mode and to gradually increase the frequency of stimulation until escape of the first “ventricular” complexes).

A special aspect of the research was to study the effect of permanent electrical pacing on the electrophysiological properties of the AV node separately from the influence of metabolic therapy in the studied time period. It is just for this reason that in each patient WPA was determined before EP implantation and after implantation, but before use of metabolic therapy and in 30 days after its cancellation, when the effect of the drug was completely neutralized. Another important task was evaluation of the extent of the influence of trimetazidine dihydrochloride on AV conduction depending on the duration of its intake and of the period after its cancellation.

Statistic processing of results of the study was performed using MedCalc 12.5.0.0 (MedCalc Software bvba, 2013), Microsoft Office Excel 2007 program. With the normal distribution of the variables, the results were presented as arithmetic means and standard deviation (M ± SD) with the indication of 95% confidence interval (CI). With the distributions of variables different from normal, the values were presented as median (Me) and interquartile range (25^th and 75^th percentiles). Student’s t-test was used to compare groups with normal distribution of variables, for distribution different from normal, non-parametric Wilcoxon test and χ2 Pearson test were used. In testing statistical hypotheses, the critical level of statistical significance was taken 0.05.

RESULTS

It was demonstrated that in the first group EP system had the following effect on WPA: on admission, the mean value of WPA in all the patients was 113.16/minute (Table 2), and in 24–48 hours after implantation of EP system — 113.03/minute (reduction by 0.11%, р = 0.161). In 6–8 hours after administration of trimetazidine dihydrochloride, the mean WPA value per minute increased by 2.05% (from 113.03 to 115.39), in 7 days — by 0.12% (from 115.39 to 115.53), in 14 days — by 1.12% (from 115.53 to 116.84), in 21 days — by 0.11% (from 116.84 to 116.97), in 30, 90, 180 days — without changes. In 7 days after cancellation of the drug, the mean WPA decreased by 0.34% (from 116.71 до 116.31), in 14 days — by 1.92% (from 116.31 to 114.08), in 21 days — by 1.15% (from 114.08 to 112.77), in 30 days — by 0.24% (from 112.77 to 112.50).

Table 2. Comparative Data of Wenckebach Point (Antegrade) of Patients of the First and Second Groups

In other words, trimetazidine dihydrochloride started to produce a positive effect on WPA already in 6–8 hours after intake, and reached the maximal effect after 3 weeks of taking; further intake did not have any additional effect on the activity of AV node either in 90, or in 180 days. The total increase in the mean WPA from the moment of 24–48 hours after EP implantation to the 180th day of taking the drug was 3.26% (р = 0.022). After cancellation of the drug, the mean WPA value decreased already in the first week and reached the minimal value on the 30^th day of cancellation (112.50, р = 0.019). In 30 days after cancellation of trimetazidine dihydrochloride, the mean WPA value decreased below the initial level: from 113.16 on admission to 112.50 in 30 days after cancellation (reduction by 0.58%, р = 0.066).

In patients of the second group, the EP system influenced the WPA in the following way: intraoperative mean WPA value was 53.20/minute, in 24–48 hours after EP implantation — 54.60/minute (increase by 2.56%, р = 0.065), in 6–8 hours after intake of trimetazidine dihydrochloride it increased by 2.71% (from 54.60 to 56.12), in 7 days — by 1.41% (from 56.12 to 56.92), in 14 days — by 0,14% (from 56.92 to 57.00), in 21 days — by 0.49% (from 57.00 to 57.28), in 30, 90, 180 days — without changes. In 7 days after cancellation of the drug, the mean WPA value decreased by 0.35% (from 57.28 to 57.08), in 14 days — by 1.89% (from 57.08 to 56.00), in 21 days — by 2.71% (from 56.00 to 54.48), in 30 days — by 4.11% (from 54.48 to 52.24).

Thus, trimetazidine dihydrochloride started to produce a positive effect on WPA already in 6–8 hours after the first intake and reached the maximal effect after 3 weeks of intake, but further intake, like in the first group, did not have any additional effect on the activity of the AV node either in 90, or 180 days. The total increase in the mean WPA from the moment of 24–48 hours after EP implantation to the 180th day of taking the preparation made 4.68% (р = 0.002). After cancellation of the drug, already in the first week, reduction of the mean WPA value was recorded which reached the minimal level on the 30^th day of cancellation of the drug (52.24, р = 0.0002). In 30 days after cancellation of trimetazidine dihydrochloride, the mean WPA value decreased below the initial value: intraoperatively, WPA was 53.20/minute, and in 30 days after cancellation of the drug — 52.24/minute (reduction by 1.8%, р = 0.109).

In patients of the third group, the following results were recorded. In 2 patients, in 21 days of trimetazidine dihydrochloride intake, antegrade AV conduction was recorded. In both patients, WPA was 65 per minute. Further observation revealed no dynamics. After cancellation of the drug, in one of these patients AV block again developed on the 7^th day, in the other — on the 14^th day. In another two patients, antegrade AV conduction was recorded on the 30^th day of taking trimetazidine dihydrochloride. In both patients, WPA was 70/minute, in further intake of the drug, no dynamics was observed. After cancellation of the drug, in one of these patients AV block developed on the 7^th day, in the other — on the 14^th day. In the rest of patients, intake of the drug did not influence antegrade AV conduction.

DISCUSSION

In two of the three studied groups, namely, in the groups of patients with SSS and II degree AV block, trimetazidine dihydrochloride had a positive effect on the antegrade AV conduction: increase in the mean WPA value from the moment of 24–48 hours after implantation of EP system to the 180th day of taking the drug was 3.26% (р = 0.022) in the first group and 4.68% (р = 0.001) in the second. In both groups, the permanent electrical cardiac stimulation did not have any effect on the activity of the AV node. The mean WPA value in the first group was 113.16/minute intraoperatively, in 24–48 hours after the ECS implantation — 113.03/minute, reduction by 0.11% (р = 0.162). In the second group, the mean WPA value on admission was 53.20/minute and 54.60/minute in 24–48 hours after ECS implantation (increase by 2.56%, but at the level of tendency — р = 0.065). In the first group, reduction of the mean WPA value by 3.82% (р = 0.019) on the 30^th day after cancellation of the drug was noted in comparison with 180^th day period of taking the drug, which corresponds to the initial figures before drug intake (р = 0.236). In the second group, reduction of WPA by 8.8% (р = 0.0002) was recorded on the 30^th day of cancellation of the drug compared to the 180-day period of taking the drug, which corresponds to the initial figures before the drug intake (р = 0.235).

To note, the maximal effect of metabolic therapy in the first and second groups was achieved after 3 weeks of taking the drug, further intake did not demonstrate any additional influence on WPA until the 180^th day.

In the third group (patients with permanent III degree AV block), trimetazidine dihydrochloride did not produce any influence on the antegrade AV conduction. It should be noted that in 4 patients of this group, despite the existence of the permanent III degree block, antegrade AV conduction still appeared (was recorded on the 21^st and 30^th day of the drug intake), although because of insufficient statistical power it is impossible to speak about statistical significance of the result (р = 0.236).

Thus, it can be concluded that the maximal effect of trimetazidine dihydrochloride manifests in patients with SSS and II degree AV block after 3 weeks of intake and persists throughout the entire follow-up period, and in 30 days after cancelation returns to the initial level. So, to maintain the positive effect, permanent intake of trimetazidine dihydrochloride is required. In patients with III degree AV block, no statistically significant positive effect was achieved.

We think that the positive effect of trimetazidine dihydrochloride is associated with prevention of reduction of the intracellular concentration of adenosine triphosphate through preservation of energetic metabolism of cells (including cells of the conducting system of the heart) in hypoxic conditions, since the preparation provides normal functioning of the membrane ion channels, transmembrane transmission of potassium and sodium ions, and preserves cell homeostasis.

In patients with angina pectoris, trimetazidine dihydrochloride increases the coronary reserve thus slowing down the onset of exercise-related ischemia, and maintains the normal blood flow through the coronary arteries including those supplying the AV node. Resting on the improvement of electrophysiological parameters in patients with bradycardia of ischemic and non-ischemic genesis, we think it reasonable to use trimetazidine dihydrochloride in this category of patients. To note, the influence of trimetazidine dihydrochloride on the electrophysiological properties in permanent electrical cardiac stimulation has not been studied before in the international and Russian literature.

CONCLUSION

Trimetazidine dihydrochloride demonstrated a positive effect on the activity of the atrioventricular node in patients with sick sinus node syndrome and II degree AV block already in 6–8 hours after its intake with the maximal effect in 3 weeks of continuous intake. To maintain this positive effect, permanent intake of the drug is required.

In patients with III degree atrioventricular lock, treatment with trimetazidine dihydrochloride did not produce a statistically significant effect on the antegrade atrioventricular conduction.

To note, the system of electrical cardiac stimulation did not produce any unfavorable effect on the atrioventricular node during the follow-up period.

ADDITIONAL INFORMATION

Funding. This study was not supported by any external sources of funding.

Conflict of interests. The authors declare no conflicts of interests.

Contribution of the authors: V. N. Smirnov ― collection and processing of material, statistical processing, writing the text; I. N. Staroverov ― research concept and design, statistical processing, editing; A. N. Gridin ― collection and processing of material, concept and research design, editing. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work.

Финансирование. Авторы заявляют об отсутствии внешнего финансирования при проведении исследования.

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

Вклад авторов: Смирнов В. Н. ― сбор и обработка материала, статистическая обработка, написание текста; Староверов И. Н. — концепция и дизайн исследования, статистическая обработка, редактирование; Гридин А. Н. — сбор и обработка материала, концепция и дизайн исследования, редактирование. Авторы подтверждают соответствие своего авторства международным критериям ICMJE (все авторы внесли существенный вклад в разработку концепции и подготовку статьи, прочли и одобрили финальную версию перед публикацией).

About the authors

Vasiliy N. Smirnov

Author for correspondence.
Email: osiber82@gmail.com
ORCID iD: 0000-0002-3314-0486
SPIN-code: 7833-8567
Russian Federation, Yaroslavl

Il’ya N. Staroverov

Email: istaroverov@mail.ru
ORCID iD: 0000-0001-9855-9467
SPIN-code: 8011-7176
ResearcherId: М-8174-2014

Dr. Sci. (Med.), Professor

Aleksandr N. Gridin

Email: angrin61@yandex.ru
ORCID iD: 0000-0002-5087-7463

Cand. Sci. (Med.)

References

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