Vol 93, No 9 (2021)

Cover Page

Full Issue


Pulmonary arterial hypertension: achievements and realities of modern treatment, a look into the future

Martynyuk T.V., Chazova I.E.


The paper summarizes the most important aspects of modern treatment of patients with pulmonary arterial hypertension (PAH): the goals of therapy are indicated, the issues of risk stratification of PAH progression/mortality, the place of combination specific therapy and switching strategies are considered, as well as new promising approaches to therapy; features of the course of the new coronavirus infection COVID-19 in this category of patients are discussed.

Terapevticheskii arkhiv. 2021;93(9):1009-1017
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Russian Medical Society for Arterial Hypertension expert consensus. Resistant hypertension: detection and management

Aksenova A.V., Sivakova O.A., Blinova N.V., Danilov N.M., Elfimova E.M., Kisliak O.A., Litvin A.Y., Oshchepkova E.V., Fomin V.V., Chikhladze N.M., Shelkova G.V., Chazova I.E.


The diagnosis of resistant arterial hypertension allows us to single out a separate group of patients in whom it is necessary to use special diagnostic methods and approaches to treatment. Elimination of reversible factors leading to the development of resistant arterial hypertension, such as non-adherence to therapy, inappropriate therapy, secondary forms of arterial hypertension, leads to an improvement in the patient's prognosis. Most patients with resistant hypertension should be evaluated to rule out primary aldosteronism, renal artery stenosis, chronic kidney disease, and obstructive sleep apnea. The algorithm for examining patients, recommendations for lifestyle changes and a step-by-step therapy plan can improve blood pressure control. It is optative to use the most simplified treatment regimen and long-acting combined drugs. For a separate category of patients, it is advisable to perform radiofrequency denervation of the renal arteries.

Terapevticheskii arkhiv. 2021;93(9):1018-1029
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Original articles

Metabolic, inflammatory and imaging biomarkers in evaluation of coronary atherosclerosis severity in patients with coronary artery disease and diabetes mellitus type 2

Koshelskaya O.A., Kharitonova O.A., Kologrivova I.V., Suslova T.E., Margolis N.Y., Tereshenkova E.K., Rybina A.N., Karpov R.S.


Aim. To study interconnections between epicardial adipose tissue thickness (EATt), parameters of glucose metabolism/insulin, C-reactive protein (hsCRP), serum adipokines and severity of coronary artery disease (CAD) depending on the presence of diabetes mellitus type 2 (DM 2); to determine significant markers of CAD severity in patients with DM 2.

Materials and methods. The study involved 106 patients with CAD (m/f – 64/42, 60.9±6.8 years), including patients with DM 2 (group 1, n=35) and non-diabetic patients (group 2, n=71). Severity of CAD was evaluated according to angiography data with calculation of Gensini Score (GS). EATt was assessed via echocardiography. Serum levels of glucose/insulin metabolism parameters, lipid fractions, hsCRP and adipokines were evaluated. Clinical parameters, including GS, did not differ between groups.

Results. EAT thickness median was elevated in gr.1 (5.1 mm vs. 4.4 mm in group 2), while adiponectin levels were decreased (6.55 µg/ml vs. 7.71 µg/ml). Linear regression of body mass index and resistin levels on EATt was revealed in gr.1; in gr.2 EATt linearly increased with waist circumference increment when EATt<6 mm. Linear regression of EATt on GS was revealed in gr.1 when EATt<8 mm, while linear regression in the whole GS range was obtained for HDL-C and hsCRP levels.

Conclusion. Study results demonstrate differences in mechanisms of deposition and functioning of epicardial and abdominal adipose tissue depending on the presence or absence of diabetic status. Patients with DM2 are characterized by the excessive EAT deposition and decrease of serum adiponectin levels compared to non-diabetic patients in the equal conditions. Independent markers of CAD severity in DM 2 are decreased HDL-C and increased hsCRP levels, but not EATt.

Terapevticheskii arkhiv. 2021;93(9):1030-1036
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Severe gastrointestinal bleeding in patients with atrial fibrillation receiving oral anticoagulants (based on REGistry of long-term AnTithrombotic TherApy – REGATTA)

Kropacheva E.S., Khakimova M.B., Krivosheeva E.N., Zemlyanskaya O.A., Panchenko E.P.


Background. The rate of major bleeding in patients with atrial fibrillation receiving oral anticoagulants is 2–5% per year. Gastrointestinal bleedings are at least a half of major hemorrhagic complications. Currently, there is no optimal scale to calculate the risk of bleeding, and therefore the search for clinical predictors of gastrointestinal bleeding remains relevant.

Aim. To assess the frequency and structure of large gastrointestinal bleeding, as well as to identify clinical predictors of their development based on long-term prospective observation of patients with atrial fibrillation receiving oral anticoagulants.

Materials and methods. Data were obtained from single center prospective REGistry of long-term AnTithrombotic TherApy (REGATTA NCT043447187). Investigation based on a 20-year follow-up with 510 patients with atrial fibrillation with a high thromboembolic risk (median CHA2DS2-VASc was 4 points). The REGATTA registry assessed the frequency and structure of major gastrointestinal bleeding. Predictors of the development of 32 large gastrointestinal bleeding were identified based on the analysis of pairs with univariate and multivariate analyses.

Results. The frequency of major gastrointestinal bleeding in patients with atrial fibrillation receiving oral anticoagulants at 1 year was 1.42 per 100 patients; the predominant localization was upper gastrointestinal tract. Predictors of the development of major gastrointestinal bleeding according to multiple regression data analysis were hemoglobin level ≤14.55 g/dL, body mass index ≤28.4 kg/m2, gastrointestinal ulcer or erosive lesion and major hemorrhagic complications in history of disease. In 1/2 cases the sourse of bleeding remained unclear.

Conclusion. Searching for clinical predictors of gastrointestinal bleeding can identify patients receiving oral anticoagulants who is need of intensive monitoring risk factors to prevent the development of life-threatening bleeding and to provide with adequate anticoagulant therapy.

Terapevticheskii arkhiv. 2021;93(9):1037-1043
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Dynamics of Holter electrocardiogram monitoring in patients with chronic heart failure and atrial fibrillation on the background of cardiac contractility modulation

Safiullina A.A., Uskach T.M., Sharapova Y.S., Kochetov A.G., Sapelnikov O.V., Tereshchenko S.N.


Aim. To evaluate the dynamics of cardiac arrhythmias on the background of cardiac contractility modulation (MCC) in patients with chronic heart failure (CHF) and various forms of atrial fibrillation (AF) on the basis of daily electrocardiogram (ECG) monitoring.

Materials and methods. In 100 patients with CHF and AF, the following studies were performed before implantation of the MCC device and after 12 months of follow-up: 12-channel ECG with an estimate of the width of the QRS complex, transthoracic echocardiography (EchoCG), and Holter ECG monitoring. All patients received long-term optimal drug therapy for CHF before surgery.

Results. The results obtained indicate that there is no effect of MCC on the development and progression of ventricular arrhythmias in patients with CHF and AF during the year of follow-up, both extrasystole and tachyarrhythmias, regardless of the etiology and LVEF (less than 35% or more than 35%), and a decrease in the frequency of AF paroxysms in patients with CHF during treatment. These results are due to the reverse remodeling of the LV myocardium under the influence of the MCC device.

Conclusion. The use of MСС in patients with CHF and AF is a safe method of therapy that does not induce cardiac arrhythmias, including ventricular extrasystole. Large-scale comparative studies are required to evaluate these results.

Terapevticheskii arkhiv. 2021;93(9):1044-1051
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Efficiency and safety of using the modified protocol for the administration of the domestic class III antiarrhythmic drug for the relief of paroxysmal atrial fibrillation

Dzaurova K.M., Mironov N.Y., Yuricheva Y.A., Vlodzyanovsky V.V., Mironova N.A., Laiovich L.Y., Malkina T.A., Zinchenko L.V., Sokolov S.F., Golitsyn S.P.


Aim. Evaluation of the efficacy and safety of the modified refralon administration protocol for the relief of paroxysmal atrial fibrillation (AF).

Materials and methods. The study included 39 patients (19 men, mean age 63±12.8 years). All patients, after excluding contraindications in the intensive care unit, were injected intravenously with refralon at an initial dose of 5 mg/kg. If AF was preserved and there were no contraindications, after 15 min, repeated administration was performed at a dose of 5 mg/kg (total dose of 10 mg/kg). After another 15 min, while maintaining AF and the absence of contraindications, the third injection of the drug was performed at a dose of 10 mg/kg (total dose of 20 mg/kg). In the absence of relief and the absence of contraindications, another injection of refralon at a dose of 10 mg/kg was performed after another 15 min (in this case, the maximum total dose of 30 mg/kg was reached). After each injected bolus and before the introduction of the next one, the ECG parameters and the general condition of the patient were assessed. The patient was monitored for 24 hours to exclude the arrhythmogenic effect and other possible adverse events.

Results. Restoration of sinus rhythm (SR) was noted in 37 patients out of 39 (95%). Of these, 19 people (48.7%) had SR recovery after the administration of a minimum dose of refralone of 5 mg/kg. The effectiveness of the total dose of 10 mg/kg was 76.9%, the dose of 20 mg/kg was 89.7%, and the dose of 30 mg/kg was 95%. Only two patients did not recover HR after administration of the maximum dose of refralon 30 mg/kg. Pathological prolongation of the QTc interval (>500 ms) was recorded in 5% of patients. Not a single case of ventricular arrhythmogenic action (induction of Torsade de pointes) has been reported. Bradyarrhythmias (pauses, bradycardia) were registered in 13% of cases, were of a transient nature.

Conclusion. Refralon has a high efficiency of relief (95%) of paroxysmal AF, while in almost half of cases (48.7%), SR recovery is achieved using the minimum dose of refralon – 5 mg/kg. Despite the prolongation of the QTc>500 ms recorded in 5% of cases, none of the patients developed Torsade de pointes after administration of the drug.

Terapevticheskii arkhiv. 2021;93(9):1052-1057
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Characteristics of patients with chronic thromboembolic pulmonary hypertension according to the Russian National Registry

Valieva Z.S., Martynyuk T.V., Nakonechnikov S.N., Chazova I.E.


Aim. To assess demographic and clinical characteristics, to describe of the functional and hemodynamic status, profile of concomitant pathology, data of instrumental examination in chronic thromboembolic pulmonary hypertension (CTEPH) patients; to study the features of specific and supportive therapy according to the data of the Russian national registry.

Materials and methods. From 2012 till 2020 a multicenter, prospective study in 15 regional expert centers of the Russian Federation (www.medibase.pro) included 404 newly diagnosed CTEPH patients over the age of 18 years in the Russian registry of patients with pulmonary arterial hypertension and CTEPH (NCT03707561). The diagnosis was established by European and Russian clinical guidelines for the diagnosis and management of pulmonary hypertension. 154 inoperable CTEPH patients an additional analysis of specific and supportive therapy was performed.

Results. The study included 404 patients (55.6% women and 44.3% men) at the age of 58.6 [48.6; 69.3] years. Median time from symptom onset to the diagnosis verification waswas 2.4 years (from 0.1 to 2.9 years). 79.1% of patients were in the III and IV functional class (World Health Organization) at the time of diagnosis and in 44.1% – with RHF (right heart failure). In assessing the profile of concomitant pathology, it was noted that CTEPH patients were more often with arterial hypertension (39.1%), erosive-ulcerative lesions of the stomach/duodenum (16.1%), atrial fibrillation (13.8%), obesity (13.1%). Distance in 6MWD (6-min walk distance) was 337.2 [250; 422] m, Borg dyspnea index scale 4.1 [3.0; 5.0] points. Hemodynamic parameters according to right heart catheterization were: Mean PAP (pulmonary arterial pressure) (51.1±14.04) mmHg, CO (cardiac output) (3.5±0.98) l/min, CI (cardiac index) (2.0±0.48) l/min/m2, PVR (2008±528) dyn×s/cm5.

Conclusion. According to the Russian registry, inoperable CTEPH patients had precapillary PH (pulmonary hypertension) with severe functional status, in combination with frequent concomitant pathology (arterial hypertension, erosive-ulcerative lesions of the stomach/duodenum, atrial fibrillation, obesity, right heart failure). 66% of inoperable CTEPH patients received specific drug therapy.

Terapevticheskii arkhiv. 2021;93(9):1058-1065
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Prognostic impact of uric acid in patients with acute decompensated heart failure

Nasonova S.N., Lapteva A.E., Zhirov I.V., Mindzaev D.R., Tereshchenko S.N.


Aim. To evaluate the prognostic impact of serum uric acid (SUA) on clinical outcomes in patients with acute decompensated heart failure, as well as identify the correlation between hyperuricemia and renal function and diuretic resistance in these patients.

Materials and methods. The study included 175 patients (125 men and 50 women) with NYHA class II–IV acute decompensated heart failure. Median age was 64 (56–75) years. The Information regarding the survival was obtained 3 years after the admission by telephone calls.

Results. 57 patients reached the end point (death from all causes); therefore, all patients were divided into groups: "alive", "dead". The SUA levels did not differ in the groups. The only significant difference in the studied parameters was the estimated glomerular filtration rate (eGFR), which was significantly higher in the "alive" group [70.5 (52.8–94) and 56 (40–79), respectively; p=0.006]. A moderate negative correlation was found between SUA levels and eGFR in the correlation analysis (r=-0.313, p<0.001). A comparative analysis showed, that SUA level on admission was significantly higher in patients who subsequently received increased doses of diuretics than in patients with a satisfactory response to standard doses of diuretics [567.8 (479.6–791.9) and 512 (422.4–619.4), respectively; p=0.011]. Also, higher eGFR level on admission was observed in patients from the normal SUA level group than in patients from the hyperuricemia group [94 (74.5–101.5) and 63 (48.8–81.3), respectively; p=0.002].

Conclusion. We found no significant differences in the uric acid level in patients who reached the end point and those who did not reach it during the three-year follow-up. However, the found correlation between uric acid levels and diuretic resistance calls for further research.

Terapevticheskii arkhiv. 2021;93(9):1066-1072
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Clinical notes

Fat cardiomyopathy in patients with severe degree of obesity. Case report

Miklishanskaya S.V., Stukalova O.V., Solomasova L.V., Mazur N.A.


Currently, the world is constantly increasing the number of people with obesity. As was shown by the Framingham study, obesity is a risk factor for many cardiovascular diseases. The effect of obesity on the structure and function of the heart is manifested in the form of cardiac remodeling, the effect on energy metabolism in the heart and infiltration of both myocardium with lipids, and an increase in the accumulation of adipose tissue in the pericardium, imbalance of adipokines and activation of inflammatory markers. Cardiac remodeling occurs primarily due to thickening of the left ventricle (LV) walls and an increase in the LV myocardium mass. Systolic dysfunction of the heart is less common in obese individuals compared with diastolic dysfunction. However, more modern methods (tissue Doppler, visualization of the deformation of the chambers of the heart – strain imaging) reveal a subclinical decrease in systolic function in people with obesity. It is not fully known whether obesity is associated with systolic dysfunction, regardless of other risk factors. In any case, it has been proven that heart failure in people with obesity can develop independently of other risk factors. As an illustration, we give an example when the presence of obesity and concomitant pathology (arterial hypertension, diabetes) led to the development of systolic dysfunction with a decrease in the LV ejection fraction to 35% (fat cardiopathy), which show the potential for the influence of both obesity itself and in combination with concomitant diseases to lead to severe systolic heart failure.

Terapevticheskii arkhiv. 2021;93(9):1073-1077
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Takotsubo syndrome after palliative transcatheter treatment of acquired aortic stenosis in patient with congenital ventricular septal defect. Case report

Komlev A.E., Muksinova M.D., Saidova M.A., Kurilina E.V., Imaev T.E.


The authors report the clinical case of secondary Takotsubo syndrome developed after transcatheter aortic valve replacement that was performed in compassionate manner in female patient with combination of congenital ventricular septal defect and acquired severe aortic stenosis. In the team’s view, Takotsubo syndrome was triggered with profound changes of intracardial hemodynamics subsequent to iatrogenic impairment of preexisting interventricular shunt.

Terapevticheskii arkhiv. 2021;93(9):1078-1085
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The clinical case of successful combined treatment of refractory arterial hypertension. Case report

Solntseva T.D., Denisova A.R., Sivakova O.A., Danilov N.M., Pevzner D.V., Chazova I.E.


In recent years, there has been an increase of patients with arterial hypertension, one of the variants of which is refractory arterial hypertension. This unfavorable clinical variant of the course of hypertension worries clinicians, due to the higher risk of developing cardiovascular complications, realizing the need for a better control of blood pressure. The presented clinical case demonstrates the successful combined treatment of refractory hypertension using antihypertensive therapy and renal denervation.

Terapevticheskii arkhiv. 2021;93(9):1086-1090
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COVID-19 and features of cardiovascular involvement

Tsyganova E.V., Glukhoedova N.V., Zhilenkova A.S., Fedoseeva T.I., Iushchuk E.N., Smetneva N.S.


The article provides an overview of current information on the pathogenesis of COVID-19 and organ-specific lesions developing in this disease. The data on inflammation and its biochemical markers, on the features of coagulopathy, endothelial damage and microthrombosis are presented in detail. Particular attention is paid to the role of receptors for angiotensin converting enzyme type 2 and transmembrane serine protease type 2 in the development of organ-specific lesions in COVID-19. The pathogenesis of damage to the cardiovascular system is considered in detail with the presentation of data from foreign literature on changes in the myocardium and the author's results of transthoracic echocardiographic examination in patients who have undergone COVID-19.

Terapevticheskii arkhiv. 2021;93(9):1091-1099
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Influenza vaccination and prognosis for patients with high cardiovascular risk

Dmitrieva O.A., Mironova O.I., Fomin V.V.


Cardiovascular and respiratory diseases have been one of the leading causes of mortality in the world for over 15 years. According to the results of various studies, a clear connection was revealed between the incidence of influenza and the decompensation of cardiovascular diseases, which leads to the development of acute coronary syndrome, acute heart failure and myocardial infarction. Also, the incidence of influenza is associated with an increase in the length of hospitalization, treatment costs and patient mortality. Influenza vaccination, especially in patients with high cardiovascular risk, is one of the most important secondary prevention measures. The article is dedicated to an overview of the problems of vaccination against influenza, the study of the prognosis of patients with high cardiovascular risk, as well as general points in the pathogenesis of influenza and cardiovascular diseases.

Terapevticheskii arkhiv. 2021;93(9):1100-1105
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Evidence base for specific pulmonary vasodilators in adults with congenital heart disease

Shmalts A.A., Gorbachevsky S.V.


After reviewing the current definitions and classification of pulmonary hypertension (PH) associated with congenital heart disease (CHD), based on an analysis of 59 clinical trials (of which 14 are randomized controlled trials) drugs registered in the Russian Federation, the evidence base for PH therapy in adults with CHD is provided. The presence of a randomized controlled trial of bosentan BREATHE-5 and uncontrolled trials of other drugs became the basis for a higher class and level of evidence of bosentan (IB) compared to other drugs (IIaC) for Eisenmenger syndrome in the current European (ERS/ESC 2015) and updated Russian (2020) guidelines. According to the updated European (ESC 2020) guidelines for congenital heart disease in adults, “in Eisenmenger patients with reduced exercise capacity (6MWT distance <450 m), a treatment strategy with initial endothelin receptor antagonist monotherapy should be considered followed by combination therapy if patients fail to improve (IIaB)”, “in low- and intermediate-risk patients with repaired simple lesions and pre-capillary PH, initial oral combination therapy or sequential combination therapy is recommended and high-risk patients should be treated with initial combination therapy including parenteral prostanoids (IA)” and “endothelin receptor antagonists and phosphodiesterase 5 inhibitors may be considered in selected patients with elevated pulmonary pressure/resistance in the absence of elevated ventricular end diastolic pressure (IIbC)”. Only three (bosentan, macitentan and selexipag) out of seven specific pulmonary vasodilators registered in the Russian Federation have indications for “pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome” or “pulmonary arterial hypertension associated with corrected simple congenital heart disease” in the instructions for use.

Terapevticheskii arkhiv. 2021;93(9):1106-1116
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Optimization of specific therapy for pulmonary hypertension: the possibilities of riociguat

Martynyuk T.V., Shmalts A.A., Gorbachevsky S.V., Chazova I.E.


Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat – for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.

Terapevticheskii arkhiv. 2021;93(9):1117-1124
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Tactics of antihypertensive therapy during COVID-19 pandemic

Podzolkov V.I., Bragina A.Е., Rodionova Y.N., Bragina G.I., Bykova E.E.


Results of foreign and Russian studies indicate a higher mortality rate of patients with concomitant cardiovascular diseases (CVD) due to the new coronavirus infection COVID-19. It has been proven that arterial hypertension, as one of the significant risk factors for the development of concomitant cardiovascular diseases, is associated with a more severe prognosis of COVID-19. This article presents the results of modern studies and large meta-analyzes of necessity and safety of the use of blockers of the renin-angiotensin-aldosterone system in patients with arterial hypertension and COVID-19. The data of studies show that an angiotensin-converting enzyme inhibitor (ACE inhibitor) and a thiazide-like diuretic is a pathogenetically rational combination. It realizes various ways of lowering blood pressure by reducing the activity of the renin-angiotensin-aldosterone system, which is achieved by using an ACE inhibitor, and natriuresis due to diuretics. As an example, a highly effective fixed combination of drugs is considered, characterized by good tolerance, which consists of an ACE inhibitor lisinopril and a thiazide-like diuretic indapamide of prolonged action. The authors expressed the opinion that the appointment of the fixed combination drug Diroton® Plus (Gedeon Richter) will contribute to effective control of blood pressure and organoprotection in conditions of increased thrombogenic and prooxidative potential, characteristic of COVID-19 both in the acute stage and within the post-COVID Syndrome.

Terapevticheskii arkhiv. 2021;93(9):1125-1131
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New clinical opportunities for mineralocorticoid receptor antagonists: focus on antifibrotic effects

Dragomiretskaya N.A., Tarzimanova A.I., Kucherova J.S., Podzolkov V.I.


Mineralocorticoid receptor antagonists have been successfully used for many years to treat patients with primary hyperaldosteronism, refractory arterial hypertension and chronic heart failure. The increased interest in this drug in recent years is due to new information about its antifibrotic and antiproliferative effects, both cardiac and extracardiac. The article also discusses the possibility of using spironolactone in patients with the new coronavirus infection SARS-CoV-2 (COVID-19).

Terapevticheskii arkhiv. 2021;93(9):1132-1137
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History of medicine

History and perspectives of the defibrillation

Isaev G.O., Vasin A.А., Mironova O.I.


History of the discovery of fibrillation and defibrillation, stages of the development of the concept of defibrillation are described in the article. The differences in mechanisms of different types of defibrillation are given here. The modern state of defibrillation and future trends are discussed in our article.

Terapevticheskii arkhiv. 2021;93(9):1138-1143
pages 1138-1143 views

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