ORIGINAL STUDIES 
Aim. To investigate the effect of ABCB1 gene carriage and interdrug interactions on apixaban pharmacokinetics and clinical outcomes in patients with atrial fibrillation and deep vein thrombosis.
Material and methods. Patients hospitalized at Yudin State Clinical Hospital participated in the study. A total of 92 patients (50 patients received apixaban and 42 – rivaroxaban) with non-valvular atrial fibrillation and deep vein thrombosis were included. Genotyping was performed by real-time polymerase chain reaction. Direct oral anticoagulants concentrations were measured using an electrospray ionization mass spectrometer in positive ionization mode.
Results. In our study we found that in patients carrying the CT+TT ABCB1 (rs4148738) C>T genotype encoding the carrier protein (P-gp), the plasma concentration of rivaroxaban was statistically significantly higher p= 0.026. In addition, we found that patients taking apixaban together with a CYP3A4/P-gp inhibitor were 3.5 times more likely to have hemorrhagic complications than those without inhibitors p = 0.004.
Conclusion. Our study revealed that the plasma concentration of rivaroxaban was higher in patients carrying the ABCB1 (rs4148738) C>T polymorphism T allele. And patients taking apixaban together with CYP3A4/P-gp inhibitor had higher risk of hemorrhagic complications in comparison with patients not taking such drugs. Further studies are needed on the influence of pharmacogenetics and pharmacokinetics on the safety and efficacy profile of apixaban and rivaroxaban, taking into account the trend of systemic approach to optimization of anticoagulant therapy of direct oral anticoagulants based on pharmacokinetic, pharmacogenetic biomarkers.
Aim. To study the levels of fibrosis markers in patients with stable coronary artery disease (CAD) and various types of coronary artery (CA) lesions (obstructive and non-obstructive), to identify possible differences for diagnosing the types of coronary obstruction.
Material and methods. The observational study included three groups of patients: with non-obstructive (main group, coronary artery stenosis <50%; n=20) and obstructive (comparison group, hemodynamically significant coronary artery stenosis according to the results of coronary angiography; n=20) CAD and healthy volunteers (control group; n=40). Transforming growth factor beta 1 (TGF-β1) and matrix metalloproteinase 9 (MMP-9) levels were measured in plasma by enzyme immunoassay. According to the results of echocardiography, all patients included in the study were divided into four groups depending on the type of myocardial remodeling.
Results. TGF-β1 levels were significantly higher in patients with obstructive CAD (p=0.008) than in patients with non-obstructive CAD and healthy volunteers (p <0.001). There were no significant differences between the main and control groups (p>0.05). There were no statistically significant differences in TGF-β1 levels depending on the type of left ventricular remodeling (p=0.139). The maximum level of MMP-9 was in the group with obstructive coronary disease and significantly differed from the main group (p <0.001) and the control group (p=0.04).
Conclusio. The maximum levels of TGF-β1 and MMP-9 were found in the group with obstructive coronary artery disease. The levels of these biomarkers in the main group were statistically different from the values obtained in the control group. Thus, considering the pathogenesis of the development of non-obstructive CAD, the use of fibrosis markers TGF-β1 and MMP-9 may be promising for diagnosing the severity of CA obstruction.
Aim. To assess the clinical outcomes and tolerability of antihypertensive therapy with single pill combinations (SPC) amlodipine + telmisartan and hydrochlorothiazide + telmisartan in clinical practice.
Material and methods. Patients with hypertension of grade 1-3 (n=13647; 57.6% women; age 59.3±11.4 years) who received therapy with SPC amlodipine + telmisartan or hydrochlorothiazide + telmisartan were included in an observational multicenter study. Information on complaints, history, previous therapy, history of novel coronavirus infection (COVID-19) during the previous year was obtained. Also, measurement of height, body weight, waist circumference (WC) and hips (HC), office blood pressure (BP) three times with an interval of 4 weeks, completion of questionnaires of satisfaction with therapy using the Likert scale, and assessement of adherence to therapy according to the patient's opinion was performed.
Results. A statistically significant decrease in systolic (SBP) and diastolic blood pressure (DBP) was found both in all patients and in the analysis of subgroups according to the grade of hypertension (p<0.001 between visits in all cases). The degree of BP reduction depended on baseline BP levels. The average decrease in SBP/DBP at the 3rd visit for the grade 1 hypertension was 24.5/14.6 mm Hg, for the grade 2 hypertension – 34.4/16.8 mmHg, for the grade 3 hypertension – 49.6/22.1 mmHg (p<0.001 between groups). Target levels of SBP (≤140 mmHg) and DBP (≤90 mmHg) were achieved in 95.3% and 98.1% of patients, respectively. Target levels of SBP (≤130 mmHg) and DBP (≤80 mmHg) were achieved in 74.9% and 78.2% of patients, respectively. WC decreased by 0.5%; HC – by 1.5%; body weight – by 0.42% (p<0.001 in all cases). Scores in patients with a history of COVID-19 did not differ from those in individuals without a history of COVID-19. There were no violations of the therapy regimen during the observation period in 94% of patients. Most doctors and patients were "satisfied" or "completely satisfied" with the clinical effect, convenience and tolerability of therapy. Adverse events occurred in 1.35% of patients.
Conclusion. Therapy with SPC amlodipine + telmisartan or hydrochlorothiazide + telmisartan in clinical practice had a high antihypertensive efficacy and had an optimal safety profile. The efficacy of therapy did not depend on the initial grade of hypertension, as well as the past infection with COVID19. The results of the ON TIME study confirm the feasibility of using the SPC amlodipine + telmisartan and hydrochlorothiazide + telmisartan for a wide range of hypertensive patients.
Aim of the study was to evaluate in a prospective cohort study the relationship between the severity of the white coat effect (WHE) in patients with hypertension, who treated with regular antihypertensive therapy, and the composite endpoint, several prognostic indicators, in a routine clinical practice.
Material and Methods. We analyzed the data of a prospective cohort study, which included 125 patients with hypertension who received regular antihypertensive therapy. The study consisted of three visits (baseline, 6 and 12 months) and an outcome data collection period (30.1±7.6 months of follow-up after the third visit). This study included three visits every 3 months: 1 visit – screening, ambulatory blood pressure monitoring (ABPM) session, Echo; 2 – assessment of the patient’s status and the therapy effectiveness; 3- assessment of the patient’s status, ABPM session, Echo (the total number of ABPM was 239, Echo - 240). The primary composite endpoint included death for any reason angina pectoris, transient ischemic attack, development of chronic heart failure, arterial revascularization, frequent ventricular extrasystoles, atrial fibrillation, secondary - deterioration of the cardiovascular diseases course and tertiary endpoint – deterioration of the arterial hypertension, concomitant diseases course.
Results. The study involved 125 patients: 28 men (22%), 97 women (78%), mean age was 62.6±0.8 years, duration of hypertension 11.6±0.8 years, height 163.6±0.7 cm, body weight 83.1±1.4 kg. The baseline mean daytime systolic BP (SBP) was 125.1±9.8 and diastolic (DBP) – 76.1±7.0 mm Hg, age was 62.8±9.0 years, the WCE level for SBP was 16.5±1.4, for DBP 10.9±0.7 mm Hg. We identified a positive correlation between tertiary composite endpoint data and WCE: for systolic WCE (SWCE) (F = 4.7, p<0.031). We found correlations between WCE and Echo parameters: 1) SWCE level had with LVMI (r = 0.16. p<0.017); 2) diastolic WCE (DWCE) had negative relationship with LV contractility parameters.
Conclusions. Thus, only systolic WCE level had correlation with composite endpoint data and LVMI. DWCE level had negative associations with echocardiography LV contractility parameters.
NOTES FROM PRACTICE 
Aim. To analyze the clinical significance of the sodium level in a single urine test obtained 2 hours after the first dose of a loop diuretic was administered in patients with acute decompensation of chronic heart failure (ADHF).
Material and methods. An observational study was conducted on the basis of a rapid-care hospital. The concentration of sodium in urine analysis obtained 2 hours after intravenous administration of the first dose of loop diuretic and natriuresis for the first day of hospitalization were evaluated. The development of resistance to diuretics was taken as the primary endpoint (the need to increase the daily dose of furosemide by more than 2 times compared to the initial one or the addition of another class of diuretic drugs).
Results. 25 patients with ADHF were included. The average age of patients was 69.0±14.8 years, 16 (64%) of them were men. The average left ventricular ejection fraction was 49.0±13.5%. The level of the N‐terminal fragment of the brain natriuretic peptide (NT-proBNP) was 3416 (2128; 5781) pg/ml. The average sodium concentration in the urine analysis obtained 2 hours after the start of treatment was 100.6±41.0 mmol / l. The concentration of sodium in urine for the first day was 102.2±39.0 mmol/l. 2 hours after the start of treatment, the sodium concentration in a single urine test was less than 50 mmol/l in 5 (20%) patients. Upon further observation, oligoanuria (defined as diuresis of less than 400 ml within 24 hours) developed in 2 of them. Oligoanuria was not detected among patients whose sodium concentration was more than 50 mmol/l. The need for escalation (any increase in the dose of a loop diuretic and/or the addition of another class of diuretic drugs) arose in 7 (28%) patients; at the same time, we diagnosed the development of resistance to diuretics in 5 (20%) of them. Resistance to diuretics was more common among patients with a sodium concentration in a single urine test obtained 2 hours after the start of furosemide administration, less than 50 mmol/l (p=0.037); when dividing the recruited patient population into subgroups with a sodium concentration in a single urine test ≥50 mmol/l and <50 mmol/l there was no significant difference in the need for any escalation of diuretic therapy [3 (60%) vs 4 (20%), p=0.07].
Conclusion. Resistance to diuretics is more common among patients with a sodium concentration in a single urine test obtained 2 hours after the first dose of furosemide, less than 50 mmol / l. Evaluation of natriuresis allows to identify insufficient effectiveness of diuretic therapy already at the beginning of treatment.
Aim. To compare the change in quality of life indicators and the main clinical and instrumental parameters in patients with chronic heart failure (CHF) and functional mitral regurgitation (FMR) under the influence of sacubitril/valsartan compared with valsartan in an outpatient practice.
Material and Methods. The study included 90 patients with chronic FMR, who were observed for 12 months. They received sacubitril/valsartan or valsartan. Efficiency criteria were: the difference between groups in scores according to the Kansas questionnaire for patients with cardiomyopathy; MR degree parameters (change in effective regurgitation orifice area, vena contracta width, MR volume and MR fraction); indicators of the severity of myocardial remodeling (left ventricular EF; the level of N-terminal brain natriuretic propeptide), exercise tolerance based on a 6-minute walk test, a change in the functional class of heart failure according to NYHA.
Results. In a treatment efficacy analysis, the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score improved by 22.1 points in the sacubitril/valsartan group and by 4.5 points in the valsartan group (p<0.001). EF, exercise tolerance, and the number of patients transitioning from NYHA functional class III to II increased in the sacubitril/valsartan group (p<0.05). Also, in this group, the effective area of the regurgitation opening, the width of the vena contracta, the volume of regurgitation, the fraction of regurgitation, and the level of N-terminal brain natriuretic propeptide (p<0.05) decreased more pronouncedly (p<0.05).
Conclusion. Compared with valsartan, treatment with sacubitril/valsartan leads to a significant improvement in the quality of life in patients with FMR and HF with reduced EF, which is largely associated with a change in NT-proBNP, echocardiographic characteristics of the severity of MR and the degree of myocardial remodeling.
Aim. To study the prevalence, clinical and endovascular predictors, causes and timing of the development of acute coronary syndrome (ACS) in patients who had previously undergone percutaneous coronary intervention (PCI), as well as the clinical features of the disease and lipid spectrum parameters.
Material and methods. The prospective study included 768 patients successively hospitalized from 01.01.2019 to 01.01.2020 in the Regional cardiovascular center, undergoing to emergency coronary angiography.
Results. The main group included 768 patients who underwent emergency coronary angiography for ACS. 90 of them had previously undergone PCI (11.7%). Men prevailed (66.7%), the average age was 62 years. 25.5% of patients underwent ACS within a year after coronary stenting, the mean time from PCI to ACS was 43 months. Most often, there was ACS without ST segment elevation (80%). The results of a retrospective analysis of the first PCI showed that 89.7% of patients underwent urgent PCI, 77.8% of patients received bare metal stents. In 67.1% of patients, 1 stent was implanted, the average diameter was 3.2 mm, the average length was 22 mm. Thromboaspiration was performed in 12% of cases, predilatation in 25%, and NC postdilation in 41.3% of cases. Complications of PCI developed in 9% of patients. Stent thrombosis was diagnosed in 7.8% of cases, significant restenosis in 35.6%. Repeated stenting due to ACS was performed in 64.4% of patients, of which 74.6% received 1 stent; average diameter 3.4 mm, average length 24.0 mm. Predilatation was performed in 52.9% of cases, thromboaspiration – in 41.2%, and NC-postdilation – in 86.7% of cases. Complications of PCI developed in 10%. In addition, 99% of patients had significant dyslipidemia. The average cholesterol level was 4.91 mmol/L, the average low-density lipoprotein level was 2.94 mmol/L.
Conclusion. Patients after PCI are 12% of group with ACS in clinical practice of the Regional Vascular Center. The most common predictor of recurrent atherothrombotic events is bare metal stent implantation as well as dyslipidemia.
Aortic valve lesion is a common and may have diverse causes, from degenerative, congenital and infectious diseases to autoimmune conditions. We present a rare case of Takayasu arteritis and severe heart lesion due to the myxomatous degeneration of the aortic and mitral valves associated with development of infective endocarditis (IE) complicated by abscess, fistula, valve perforation and recurrent acute decompensated heart failure in a young female patient. A combined use of histopathological and PCR analyses of valve tissues was critically important for differential diagnosis of the valve lesions, as it made it possible to identify the true cause of the disease. The presence of Takayasu arteritis has played an indirect role by creating conditions for the development of immunosuppression and determining the disease severity and its progression.
PAGES OF RUSSIAN NATIONAL SOCIETY OF EVIDENCE-BASED PHARMACOTHERAPY 
Aim. The aim of the research is to evaluate the relationship between patients' adherence to visiting polyclinics after acute coronary syndrome (ACS) and the quality of the therapy they receive.
Material and methods. The study was conducted on the basis of the LIS registers (LIS and LIS-3) (Lyubertsy study of mortality) in the Lyubertsy district of the Moscow region. To clarify the vital status of all patients discharged in the first 9 months of 2014 and 2018. from Lyubertsy district hospital 2, contact was established no earlier than 1 year after discharge, and in case of death, its cause was clarified. In the course of a telephone survey, information was obtained on the therapy taken, adherence to visits to medical institutions, a record of cases of cardiovascular events and invasive treatment, hospitalizations due to worsening of the course of the underlying disease for the period after discharge from the hospital was carried out. The search for patients who did not answer the phone call was carried out by studying the archives of polyclinics, using the Megaclinic statistical database, and the data of the individual rehabilitation program for the disabled. In the course of a telephone survey, the response was 60.5%, the search for the remaining patients through statistical databases, the archive of polyclinics made it possible to increase the total response to 87.2%.
Results. In the LIS-3 registry, out of 104 patients discharged in 2014, the status was determined in 90 (86.5%) patients, out of 223 patients in 2018 – in 195 (87.4%) patients. During the survey, it was found that 172 patients are observed after discharge from the hospital, 53 patients are not observed at all in the medical facility after discharge. 11 (4.9%) people did not take any groups of medications at the time of the survey. In the group of patients who are highly committed to attending a health facility, the best quality of taking essential medications after discharge from the hospital was noted according to the survey: statins (88.2%, p<0.001), beta-blockers (86.4%, p<0.001) and antiplatelets (90.9%, p=0.001). In both groups, committed and not committed to attending a medical facility, there is a negative dynamics in the quality of taking medications after discharge from the hospital, however, in the group of patients committed to attending a medical facility, it was noted that the odds of taking antiplatelet agents after discharge was 3.4 times higher (OR 3.449, p=0.002), beta-blockers – 4 times (OR 4.103, p<0.001), statins – 4.5 times (OR 4.450, p<0.001), in relation to the group of patients who are not observed in the medical facility after discharge from the hospital.
Conclusion. 1-6 years after discharge from the hospital after the reference event, the quality of therapy deteriorated significantly in both groups, mostly in non-adherent patients. Significant differences in the quality of medication intake (antiplatelet agents, statins, β-blockers) were noted in the group of adherents to visiting health care facilities in comparison with those who were not committed to visiting health facilities. It is obvious that high adherence to visits to healthcare facilities after discharge from the hospital is associated with better quality of medication intake. Despite improvements in the quality of adherence to clinical recommendations, the percentage of patients who independently refuse to take drug therapy (4.9%), regardless of visits to healthcare facilities after discharge from the hospital, remains.
POINT OF VIEW 
The population of Japan and Okinawa is known for the longest life expectancy, which many researchers rightly associate with the nature of nutrition existing in these territories. The Japanese diet and Okinawan diet, along with other traditional diets, are real examples of historically established sustainable patterns of healthy eating. Asian eating styles have marked differences from European eating patterns, not only in differences in food sources, but also in eating habits. The article presents the historical, climatic and cultural features of these diets; the issues of food composition, energy and nutritional value of these models of nutrition are considered in detail with an analysis of the differences existing between them; highlights the benefits of products grown mainly in Japan, which are ration-forming for the population of this country; as well as the results of scientific studies on the protective effect of the Japanese and Okinawan diets on human health and disease prevention.
The work of the national network of vascular centers of the Russian Federation (RF), based on the Clinical recommendations of the Russian Society of Cardiology and the procedure for providing medical care to patients with cardiovascular diseases, has led to significant positive results in the treatment of patients with acute coronary syndrome (ACS) in the country, although a number of targets have not yet been reached. The purpose of the publication is to demonstrate the trend in therapeutic approaches to the management of patients with ACS in 2020-2022. in Russia and analysis of their effectiveness. Quantitative and qualitative indicators of the treatment of patients with ACS for the presented analysis were obtained on the basis of monitoring data from the Russian Ministry of Health for 2018-2021. presented: Monitoring of measures to reduce mortality from coronary heart disease, letters of the Ministry of Health of Russia dated March 13, 2015 No. 17-6 / 10 / 1-177 and dated July 24, 2015 No. 17-9 / 10 / 2-4128, within which data collection carried out monthly, on the portal of the Federal State Budgetary Institution "TsNIIOIZ" of the Ministry of Health of Russia - Automated system for monitoring medical statistics and the register REGION-IM (Russian Register of Acute Myocardial Infarction) - a multicenter prospective observational cohort study for 2020-2022, organized by the Federal State Budgetary Institution "National Medical Research Center of Cardiology named after Academician E.I. Chazov" of the Ministry of Health of Russia. In Russia with a diagnosis of ACS in 2020 and 2021 403,931 and 397,930 patients were hospitalized, respectively. The decrease in the number of patients diagnosed with ACS admitted to Russian hospitals by 22.32% was mainly due to a significant decrease in hospital admissions of patients diagnosed with non-ST elevation ACS (non-STE-ACS) (by 29.03%). At the same time, the admission of patients with ST elevation myocardial infarction (STEMI) decreased only by 6.02%. Compared to 2018-2019, in 2020-2022. increased mortality in primary percutaneous coronary intervention (PCI) (by 9.6%) and in the general STEMI group (by 12.3%); significantly increased mortality both in the general group of NSTE-ACS (by 48%) and during PCI for patients with non-STE-ACS (by 28.6%); there was an increase in the average annual number of primary PCI (by 12.6%); an absolute and relative increase in the number of PCI in non-STE-ACS was revealed (by 2.7 and 37.1%, respectively). In the country's hospitals, by the time of discharge, 95% of patients receive statins, beta-blockers – 87%, ACE inhibitors – 80%, acetylsalicylic acid – 82%, P2Y12 inhibitors – 98% of patients, regardless of the type of ACS. In Russia in 2020-2022 unfavorable tendencies in the provision of care to patients with ACS include: increased mortality in primary PCI and in the general STEMI group; increased mortality both in the general group of non-STE-ACS and during PCI for patients with non-STE-ACS. The positive results of the work of the national network of vascular centers include: absolute, relative and estimated increase in the number of primary PCI; absolute and relative increase in the number of PCI in non-STE-ACS; a high level of prescribing drugs with a proven positive effect on the prognosis.
High mortality from cardiovascular diseases (CVD) requires improved approaches to the treatment of this socially significant pathology. Wide implementation of surgical myocardial revascularization makes it possible to improve significantly both life quality and expectancy in patients with coronary heart disease. The aim of this work was to analyze the literature on the impact of preoperative, operative and postoperative factors on the long-term prognosis after coronary artery bypass grafting (CABG). The review refers to both recent and earlier informative works. The target groups for this article are therapists, cardiologists, rehabilitologists, who work with patients in the short and long term after CABG. Data of Russian and foreign literature show that the long-term prognosis after CABG is largely determined by preoperative factors, in particular – age, set of cardiovascular risk factors (RF) and comorbidity, specifically – severity of coronary and systemic atherosclerosis, incident cardiovascular complications, structural and functional state of the heart. In the aggregate these factors reflect the cumulative effect and further potential of actual cardiovascular RFs, affect longterm risk of adverse events, and determine the therapeutic targets of secondary prevention. Priority of arterial conduits and completeness of revascularization are the main operative factors that determine the course of the long-term period after CABG. Among the postoperative factors, the efficiency of secondary CVD prevention is of paramount importance, in particular – achievement of target RF levels, compensation of cardiac and extracardiac pathology, adherence to the long-term medical therapy, known to improve outcomes based on specific comorbidity. Efficiency of secondary CVD prevention largely depends on patient's health attitudes, the key influence on which beyond attending physician can be provided by participation in rehabilitation programs, teaching patients the meaning and essentials of lifestyle modification and cardiovascular RFs’ control.
CURRENT QUESTIONS OF CLINICAL PHARMACOLOGY 
Currently, antithrombotic therapy is the basis of the pathogenetic treatment of many cardiovascular diseases, such as coronary heart disease, stroke, peripheral vascular disease, as well as mechanical heart valves, heart rhythm disturbances, venous thromboembolism. At the same time, chronic use of antiplatelet and/or anticoagulant drugs is a complicating factor in invasive and surgical procedures, as it increases the risk of bleeding. In this regard, a fundamentally important and complex question arises: how to minimize the risk of periprocedural bleeding without exposing the patient to an increased risk of ischemic and thromboembolic complications? Perioperative management of patients who take antithrombotic drugs for a long time is a complex problem that depends on many factors - the risk of surgery, anesthesia, cardiovascular risks, and the urgency of surgery. Each clinical situation should be assessed individually, collegially, with the participation of surgeons, anesthesiologists, and therapists. The introduction of a checklist into clinical practice for each planned surgical patient will allow us to calculate the individual risk of bleeding and thromboembolic complications, and provide an optimal preventive strategy for perioperative management of the patient. The algorithms and schemes presented in the article for the perioperative management of patients with non-cardiac interventions are aimed at standardizing the management of patients before non-cardiac surgical interventions, which will reduce hemorrhagic risks in the presence of the necessary antithrombotic therapy.
Left ventricular thrombus (LVT) is a serious risk factor for systemic embolism development. Despite the evident danger of this condition, current guidelines describe management of patients with this potentially fatal complication very briefly. LVT can complicate myocardial infarction where its incidence is around 10%, as well as various forms of cardiomyopathies and novel coronavirus infection. According to clinical guidelines vitamin K antagonists (VKAs) should be used as treatment of choice for thrombus resolution. However, experts point out that this therapy lacks necessary evidential base and bears certain difficulties because of pharmacokinetic and pharmacodynamical properties of VKAs. These drawbacks are absent in direct oral anticoagulants (DOACs), the possibility of using which in LVT is being actively studied. As for now, published results of 3 randomised clinical trials have demonstrated similar safety and efficacy profiles of DOACs and VKAs. Similarly, the majority of retrospective cohort studies did not observe significant differences between two groups, where some of them have shown superiority of DOACs especially in terms of earlier thrombus resolution. Nevertheless, some studies have found DOACs ineffective and even potentially unsafe regarding systemic embolism. Existing data does not allow to form an unambiguous conclusion about the equivalence of DOACs and VKAs for LVT resolution. Large randomised clinical trials are needed to determine efficacy and safety of such treatment in these patients.
The modern cardiology has a wide range of medications which affect various pathogenetic links of atherosclerosis, but even the best of them still obtain disadvantages causing intolerance and medicine discontinuation. The development of new hypolipidemic medications will allow not only to introduce alternative therapies into the cardiology practice, but also to completely execute the strategy of residual risk reduction by utilizing rational combinations of medications. One of such alternatives could be bempedoic acid, which can have a positive effect on a number of endpoints as the results of third phase trials have shown. These effects are also confirmed in Mendelian randomization studies. The mechanism of action of bempedoic acid is presumably associated with inhibition of the activity of ATP citrate lyase – the enzyme responsible for the breakdown of citrate into acetyl-CoA and oxaloacetate. Acetyl-CoA, in turn, is used by the cell to synthesize cholesterol and fatty acids. Thus, bempedoic acid affects in the same metabolic pathway as statins, but at an earlier stage. According to this, it is possible that medications of these classes will have similar side effects and pleiotropic effects associated with modulation of the mevalonic pathway, such as prenylation regulatory proteins (small GTPases) or reduction of coenzyme Q synthesis. However, there are also some specific features of the pharmacodynamics and pharmacokinetics of bempedoic acid to be considered. In particular, once entered the body, it must be activated via esterification by very long-chain acyl-CoA synthetase-1. The enzyme isoform required for this process is expressed in a tissue-specific manner and, for example, is absent in skeletal myocytes. In addition, citrate, oxaloacetate, and acetyl-CoA are important regulators of many intracellular processes: metabolism, growth and proliferation, mechanotransduction, posttranslational modifications of histones and other proteins. The levels of all three substances are altered by bempedoic acid, although no firm conclusions about the effects of these changes can be drawn at this time. The mentioned features probably have a significant impact on the clinical profile of bempedoic acid and underlie the differences from statins already observed in third phase trials, including, for example, a reduced risk of the onset or worsening of diabetes mellitus while taking bempedoic acid.
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