RU2716479C1 - Method for prediction of response to cardiac resynchronising therapy in patients with chronic heart failure - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to clinical cardiology, and can be used for prediction of the response to cardiac resynchronizing therapy in the patients with chronic cardiac failure. It is followed by echocardiography. Left ventricular ejection fraction is determined in echocardiography in %. Patient is additionally examined for cystatin C in ng/l, matrix metalloproteinase in ng/l, C-reactive protein in ng/l in blood. Based on the obtained data, the value of the function F is determined: F=3.231+0.344×EF-3.479×CYSTATIN-0.039×MMP9-0.638×CRB, where EF – left ventricular ejection fraction, %, CYSTATIN - level of cystatin C in ng/l, MMP9 – level of matrix metalloproteinase – 9 in ng/l, CRB – level of C-reactive protein in ng/l. Cardiac resynchronization therapy (P) response is predicted: P=1/(1+e^(-F)). If P is less than 0.696, belonging to a group of nonresponders is determined. If P is greater than or equal to 0.696, belonging to a group of responders is determined and a response to a cardiac resynchronization therapy is predicted.

EFFECT: method enables accurate, quick and simple prediction of developing a response to cardiac resynchronization therapy by a mathematical model of logistic regression based on results of echocardiographic examination and laboratory analysis using.

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Description

The invention relates to the field of medicine, namely to clinical cardiology, is aimed at increasing the efficiency of treatment of patients with chronic heart failure (CHF), improving the selection of patients for cardiac resynchronization therapy (CPT).

С, Mazzanti A., Blom N., Borggrefe M, Camm J., Elliott P.M., Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck K.H., Hernandez-Madrid A., Nikolaou N.,

T.M., Spaulding C, Van Veldhuisen D.J. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace (2015); 17 (11): 1601-87]. Для отбора на СРТ используется ряд критериев: II-IV функциональный класс ХСН по классификации NYHA, снижение фракции выброса левого желудочка (ФВЛЖ) менее 35%, расширение комплекса QRS электрокардиограммы, наличие блокады левой ножки пучка Гиса, несмотря на адекватное медикаментозное лечение [Мареев В.Ю., Агеев Ф.Т., Арутюнов Г.П., Коротеев А.В., Мареев Ю.В., Овчинников А.Г., Беленков Ю.Н., Васюк Ю.А., Галявич А.С., Гарганеева А.А., Гиляревский С.Р., Глезер М.Г., Козиолова Н.А., Коц Я.И., Лопатин Ю.М., Мартынов А.И. (президент РНМОТ), Моисеев B.C., Ревишвили А.Ш., Ситникова М.Ю., Скибицкий В.В., Соколов Е.И., Сторожаков Г.И., Фомин И.В., Чесникова А.И., Шляхто Е.В. (президент РКО). Национальные рекомендации ОССН, РКО и РНМОТ по диагностике и лечению хронической сердечной недостаточности (четвертый пересмотр). Сердечная недостаточность. 2013; 14: 7(81), Ревишвили А.Ш., Ардашев А.В, Бойцов С.А., Бокерия О.Л., Голухова. Е.З., Давтян Ю.Н., Зенин С.А., Кузнецов В.А., Купцов В.В., Лебедев Д.С., Ломидзе Н.Н., Медведев М.М., Недоступ А.В., Неминущий Н.М., Певзнер А.В., Покушалов Е.А., Рзаев Ф.Г., Сопов О.В., Сулимов В.А., Сыркин А.Л., Термосесов С.А., Тюрина Т.В., Шубик Ю.В., Яшин С.М. Клинические рекомендации по проведению электрофизиологических исследований, катетерной абляции и применению имплантируемых антиаритмических устройств. Новая редакция. М.: 2013; 96-127; Priori S.G,

С, Mazzanti A., Blom N., Borggrefe M., Camm J., Elliott P.M., Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck K.H., Hernandez-Madrid A., Nikolaou N., Norekval T.M., Spaulding C.,Van Veldhuisen D.J. et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace (2015); 17 (11): 1601-87. doi: 10.1093/eurheartj/ehv316]. Многочисленные многоцентровые рандомизированные исследования, посвященные оценке эффективности СРТ, свидетельствуют об улучшении качества жизни, увеличении продолжительности жизни, снижении частоты госпитализации по поводу прогрессирования сердечной недостаточности, смертности от ХСН и общей смертности [Priori S.G,

С, Mazzanti A., Blom N., Borggrefe M., Camm J., Elliott P.M., Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck K.H., Hernandez-Madrid A., Nikolaou N.,

T.M., Spaulding C., Van Veldhuisen D.J. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace (2015); 17(11): 1601-87].At present, CPT is the “gold standard” for the treatment of patients with moderate and severe CHF with an expanded QRS complex [Priori SG,

C, Mazzanti A., Blom N., Borggrefe M, Camm J., Elliott PM, Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck KH, Hernandez-Madrid A., Nikolaou N.,

TM, Spaulding C, Van Veldhuisen DJ 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace (2015); 17 (11): 1601-87]. For the selection for CPT, a number of criteria are used: IIHA functional class of CHF according to NYHA classification, a decrease in the left ventricular ejection fraction (LVEF) of less than 35%, an expansion of the QRS complex of an electrocardiogram, the presence of a blockade of the left bundle of His, despite adequate drug treatment [Mareev V .Yu., Ageev F.T., Arutyunov G.P., Koroteev A.V., Mareev Yu.V., Ovchinnikov A.G., Belenkov Yu.N., Vasyuk Yu.A., Galyavich A.S. ., Garganeeva A.A., Gilyarevsky S.R., Glezer M.G., Koziolova N.A., Kots Y.I., Lopatin Yu.M., Martynov A.I. (President of RNMOT), Moiseev BC, Revishvili A.Sh., Sitnikova M.Yu., Skibitsky V.V., Sokolov E.I., Storozhakov G.I., Fomin I.V., Chesnikova A.I., Shlyakhto E.V. (President of the CSC). National Recommendations of ASCH, RKO and RNMOT for the diagnosis and treatment of chronic heart failure (fourth revision). Heart failure. 2013; 14: 7 (81), Revishvili A.Sh., Ardashev A.V., Boytsov S.A., Bokeria O.L., Golukhov. E.Z., Davtyan Yu.N., Zenin S.A., Kuznetsov V.A., Kuptsov V.V., Lebedev D.S., Lomidze N.N., Medvedev M.M., Inaccessibility A. V., Neminuschiy N.M., Pevzner A.V., Pokushalov E.A., Rzayev F.G., Sopov O.V., Sulimov V.A., Syrkin A.L., Thermoses S.A. , Tyurina T.V., Shubik Yu.V., Yashin S.M. Clinical recommendations for electrophysiological studies, catheter ablation and the use of implantable antiarrhythmic devices. New edition. M .: 2013; 96-127; Priori SG,

C, Mazzanti A., Blom N., Borggrefe M., Camm J., Elliott PM, Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck KH, Hernandez-Madrid A., Nikolaou N., NorekvalTM, Spaulding C., Van Veldhuisen DJ et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace (2015); 17 (11): 1601-87. doi: 10.1093 / eurheartj / ehv316]. Numerous multicenter randomized trials to evaluate the effectiveness of CRT indicate an improvement in the quality of life, increase in life expectancy, and a decrease in the hospitalization rate due to progression of heart failure, mortality from heart failure, and general mortality [Priori SG,

C, Mazzanti A., Blom N., Borggrefe M., Camm J., Elliott PM, Fitzsimons D., Hatala R., Hindricks G., Kirchhof P., Kjeldsen K., Kuck KH, Hernandez-Madrid A., Nikolaou N.,

TM, Spaulding C., Van Veldhuisen DJ 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace (2015); 17 (11): 1601-87].

A.R., Oshinski J.N. Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation. 2010, 11; 121(18):1985-91. doi: 10.1161/CIRCULATIONAHA.109.910778]. Наиболее широко используемым и доказавшим свою высокую прогностическую ценность в оценке ответа показателем является снижение конечно-систолического объема левого желудочка (КСОЛЖ) 15% и более от исходного по результатам двухмерной эхокардиографии. Пациенты с уменьшением КСОЛЖ менее 15% считаются нереспондерами, то есть неответчиками на СРТ [Chung Е. S., Leon A. R., Tavazzi L., Sun J.P., Nihoyannopoulos P., Merlino J., Abraham W.T., Ghio S., Leclercq C, Bax J.J., Yu С.М., Gorcsan J. 3rd, St John Sutton M., De Sutter J., Murillo J. Results of the predictors of response to CRT (PROSPECT) trial. Circulation, 2008; 117(20): 2567-2569. doi: 10.1161/CIRCULATIONAHA.107.743120]. По данным доступной литературы количество нереспондеров достигает 30% [Daubert С, Behar N., Martins R P., Mabo P., Leclercq C. Avoiding non-responders to cardiac resynchronization therapy: a practical guide. European heart journal. 2016; 38(19): 1463-1472. doi: 10.1093/eurheartj/ehw270; Dhesi S, Lockwood E, Sandhu R.K. Troubleshooting Cardiac Resynchronization Therapy in Non-responders, Canadian Journal of Cardiology, 2017. doi: 10.1016/j.cjca.2017.04.007; Zhang Q., Zhou Y., Yu С.M. Incidence, definition, diagnosis, and management of the cardiac resynchronization therapy nonresponder. Curr opin cardiol 2015; 30 (1): 40-9]. Известно, что нереспондеры имеют более высокий риск общей смертности, повышенный риск развития сердечно-сосудистых событий и жизнеугрожающих нарушений ритма сердца в сравнении с респондерами [Rickard J., Baranowski В., Wilson Tang W.H., Grimm R.A., Niebauer M., Cantillion D., Varma N. Echocardiographic Predictors of Long-Term Survival in Patients Undergoing Cardiac Resynchronization Therapy: What Is the Optimal Metric?. Journal of Cardiovascular Electrophysiology. 2017; 28(4): 410-415; Zhang Q., Zhou Y., Yu С.M. Incidence, definition, diagnosis, and management of the cardiac resynchronization therapy nonresponder. Curr opin cardiol 2015; 30 (1): 40-9]. В связи с чем проблема недостаточного ответа на СРТ является очень актуальной.Various criteria can be used to assess the effectiveness of CPT, such as indicators of clinical response, functional criteria, laboratory markers, or a combination of these when using combined models [Recommendations on heart failure; Rickard J., Baranowski B., Wilson Tang WH, Grimm RA, Niebauer M., Cantillion D., Varma N. Echocardiography Predictors of Long-Term Survival in Patients Undergoing Cardiac Resynchronization Therapy: What Is the Optimal Metric ?. Journal of Cardiovascular Electrophysiology. 2017; 28 (4): 410-415; Fornwalt BK, Sprague WW, BeDell P., Suever JD, Gerritse B., Merlino JD, Fyfe DA,

AR, Oshinski JN Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation. 2010, 11; 121 (18): 1985-91. doi: 10.1161 / CIRCULATIONAHA.109.910778]. The most widely used indicator that has proved its high prognostic value in assessing the response is a decrease in the end-systolic volume of the left ventricle (LVSC) of 15% or more from the initial one according to the results of two-dimensional echocardiography. Patients with a decrease in LVEF of less than 15% are considered non-responders, that is, non-responders to CPT [Chung E. S., Leon AR, Tavazzi L., Sun JP, Nihoyannopoulos P., Merlino J., Abraham WT, Ghio S., Leclercq C, Bax JJ, Yu S.M., Gorcsan J. 3rd, St John Sutton M., De Sutter J., Murillo J. Results of the predictors of response to CRT (PROSPECT) trial. Circulation, 2008; 117 (20): 2567-2569. doi: 10.1161 / CIRCULATIONAHA.107.743120]. According to available literature, the number of non-responders reaches 30% [Daubert C, Behar N., Martins R. P., Mabo P., Leclercq C. Avoiding non-responders to cardiac resynchronization therapy: a practical guide. European heart journal. 2016; 38 (19): 1463-1472. doi: 10.1093 / eurheartj / ehw270; Dhesi S, Lockwood E, Sandhu RK Troubleshooting Cardiac Resynchronization Therapy in Non-responders, Canadian Journal of Cardiology, 2017. doi: 10.1016 / j.cjca.2017.04.04.007; Zhang Q., Zhou Y., Yu S.M. Incidence, definition, diagnosis, and management of the cardiac resynchronization therapy nonresponder. Curr opin cardiol 2015; 30 (1): 40-9]. Non-responders are known to have a higher risk of overall mortality, an increased risk of developing cardiovascular events and life-threatening cardiac arrhythmias compared to responders [Rickard J., Baranowski B., Wilson Tang WH, Grimm RA, Niebauer M., Cantillion D. , Varma N. Echocardiographic Predictors of Long-Term Survival in Patients Undergoing Cardiac Resynchronization Therapy: What Is the Optimal Metric ?. Journal of Cardiovascular Electrophysiology. 2017; 28 (4): 410-415; Zhang Q., Zhou Y., Yu S.M. Incidence, definition, diagnosis, and management of the cardiac resynchronization therapy nonresponder. Curr opin cardiol 2015; 30 (1): 40-9]. In this connection, the problem of insufficient response to CPT is very urgent.

Since the first publication of the recommendations for the treatment of heart failure and implantation of devices for CPT, there have been significant changes, additional selection criteria have been introduced. However, the use of more stringent criteria for the selection of patients for CPT by the duration and morphology of QRS led to a decrease in the use of CPT without increasing the level of good response [Sade L.E. Standards and options - How to predict and measure CRT success? EuroEcho-Imaging 2017]. The percentage of patients who do not respond to CPT, even during selection, taking into account all generally accepted selection criteria, remains high. In this connection, the search for new additional selection criteria for CPT that will improve the quality of selection and reduce the number of non-correspondents is one of the most important tasks of CPT application.

In addition, it remains not completely clear at what time after implantation it is necessary to evaluate the response to therapy. The accumulated experience in implanting resynchronization devices demonstrates that the timing of the best response is very individual. Some patients demonstrate a quick response to CRT with pronounced positive dynamics of clinical and functional parameters within the first three months after implantation, in other patients the response time is longer [Kuznetsov V.A., Melnikov N.N., Krinochkin D.V., Kolunin G.V., Gorbatenko E.A. Acute hemodynamic effect of cardiac resynchronization therapy in patients with chronic heart failure. Bulletin of arrhythmology. 2013; 74: 50-54; Ghio S., Freemantle N., Scelsi L., Serio A., Magrini G., Pasotti M. et al. Long-term left ventricular reverse remodeling with cardiac resynchronization therapy: results from the CARE-HF trial. European journal of heart failure. 2009; 11 (5): 480-488.]. According to some authors, an early response to CPT is associated with a degree of reversibility of heart remodeling in the long-term follow-up, however, other larger studies did not reveal such a relationship [Prinzen F.W., Auricchio A. The "missing" link between acute hemodynamic effect and clinical response. Journal of cardiovascular translational research. 2012; 5 (2): 188-195; Mullens, W., Verga, T., Grimm, R. A. Starling R. C, Wilkoff B. L., Tang W. W. Persistent hemodynamic benefits of cardiac resynchronization therapy with disease progression in advanced heart failure. Journal of the American College of Cardiology, 2009; 53 (7): 600-607]. Some patients whose response develops in the long-term follow-up period (more than 12 months) during the first year do not demonstrate positive dynamics of LVSC, increased LVEF and can be identified as non-responders [Kuznetsov V.A., Soldatova AM, Krinochkin D.V. , Enina T.N. Cardiac resynchronization therapy for chronic heart failure: should I wait for a quick response? Journal of Heart Failure. 2017; 18 (3): 172-177. DOI: 10.18087 / rhfj.2017.3.2341; _Burns K. V., Gage R. M., Curtin A.E., Bank A. J. Long-term echocardiographic response to cardiac resynchronization therapy in initial nonresponders. JACC: Heart Failure, 2015; 3 (12), 990-997; Ellenbogen K. A., Kron J. Delayed Response to Cardiac Resynchronization: Better Late Than Never. JACC: Heart Failure. 2015. T. 3 (12): 998-1000]. Earlier in our works, we showed that the assessment of the response in strictly fixed terms is not entirely correct and can overestimate the number of non-responders [Soldatova A.M., Kuznetsov V.A., Krinochkin D.V., Enina T.N., Gorodniuk I.G. Late best response to cardiac resynchronization therapy is associated with better survival of patients with congestive heart failure. Current Research Cardiology. 2017; Vol 4 (4): 58-60; Kuznetsov V.A., Soldatova A.M., Krinochkin D.V., Enina T.N. Whether we should expect for an early response to cardiac resynchronization therapy. Eur Heart J Cardiovasc Imaging Abstracts Supplement (December 2017). P607: iii132]. In this connection, the approach not only to the selection of such patients, but also to their further management after implantation should be very individual and comprehensive with the assessment of clinical and functional indicators throughout the observation period.

Among the many mechanisms involved in the development of heart failure, the researchers pay close attention to the study of processes of immune inflammation and myocardial fibrosis.

Activation of the processes of immune inflammation in CHF initially has an adaptive-compensatory value. Mediators of immune inflammation are cytokines (tumor necrosis factor-α, C-reactive protein (CRP), interleukins). With the progression of CHF, excessive production of cytokines is observed, which are capable of exerting a cardiodepressive, powerful negative inotropic effect, as well as a direct toxic effect on the myocardium. A close relationship was found between cytokine levels and the severity of clinical manifestations of CHF [Chaturvedi P., Kalani A., Familtseva A., Kamat P.K., Metreveli N., Tyagi S.C. Cardiac tissue inhibitor of matrix metalloprotease 4 dictates cardiomyocyte contractility and differentiation of embryonic stem cells into cardiomyocytes: Road to therapy. Int J Cardiol. 2015 Apr 1; 184: 350-63. doi: 10.1016 / j.ijcard.2015.01.09.091; 29; Hofmann U., Frantz S. How can we cure a heart "in flame"? A translational view on inflammation in heart failure. Basic research in cardiology, 2013; 108 (4): 1-19. doi: 10.1007 / s00395-013-0356-y; Gullestad L., Ueland T., Vingeet L.E., Finsen A., Yndestad A., Aukrust P. Inflammatory cytokines in heart failure: mediators and markers. Cardiology, 2012; 122 (1): 23-35. doi: 10.1159 / 000338166]. Increased production of cytokines stimulates the development of fibrosis due to increased apoptosis of cardiomyocytes, helps to increase the synthesis of matrix metalloproteinases, in particular matrix metalloproteinases - 9 (MMP-9), which causes degradation of collagen and all extracellular cardiac matrix, which is accompanied by dilatation of the cardiac cavities and leads to even more rapid dilatation of the heart CHF [Kuznetsov V. A., Soldatova A. M., Enina T. N., Petelina T. N. Natriuretic peptide and inflammatory mediators in patients with different responses to cardiac resynchronization therapy. Journal of Heart Failure. 2015; 16 (2): 88-92. DOI: 10.18087 / rhfj.2015.2.2047].

One of the newer early biomarkers for assessing the severity and progression of heart failure is cystatin C. This is a small protein from the family of cysteine protease inhibitors, the main biological role of which is associated with the suppression of the activity of extracellular cactepsins. Cystatin C is a strong and independent predictor of cardiac mortality in patients hospitalized with severe heart failure and having normal or mildly impaired renal function, including patients with implanted CPT devices [Iwanaga Y., Miyazaki S. Heart failure, chronic kidney disease , and biomarkers. Circ. J. 2010; 74 (7): 1274-1282; Moran A., Katz R., Smith N. L., Fried L. F., Sarnak M. J., Seliger S. L., Psaty B., Siscovick D. S., Gottdiener J. S., Shlipak M. G. Cystatin With concentration as a predictor of systolic and diastolic heart failure. J. Card. Failure. 2008; 14 (1): 19-26. doi: 10.1016 / j.cardfail.2007.09.09.002; Ruan Z.B., Chen G.C., Ren Y., Zhu L. Prediction efficiency of serum cystatin C for clinical outcome in patients with cardiac resynchronization therapy. Irish Journal of Medical Science (1971-,), 2018; 1-6.

T, Matana

Z (2014) Can the difference in serum concentration of urea and cystatin С be used in diagnosis and prognosis of heart failure? Med Hypotheses 83:401-403]. Согласно исследованию U. Alehagen и соавт., измерение цистатина С в сочетании с NT-proBNP является значимой комбинацией биомаркеров для прогнозирования кардиоваскулярной смертности у пациентов с сердечной недостаточностью [Alehagen U., Dahlstrom U., Lindahl T.L. Cystatin С and NTproBNP, a powerful combination of biomarkers for predicting cardiovascular mortality in elderly patients with heart failure: results from a 10-year study in primary care. Eur. J. Heart Failure.2009; 11 (4): 354-360. doi: 10.1093/eurjhf/hfp024].https://doi.org/10.1007/s11845-018-1771-8; Yamamoto T., Shimano M., Inden Y., Miyata S., Inoue Y., Yoshida N., Tsuji Y., Hirai M., Murohara T. Cystatin C as a predictor of mortality and cardiovascular morbidity after cardiac resynchronization therapy. Circ J. 2013; 77 (11): 2751-6. doi: 10.1253 / circj.CJ-13-0179]. Some researchers believe that the level of cystatin C is linearly associated with the risk of progression of heart failure, and the degree of risk of rapid progression of diastolic heart failure can be judged by the appearance of high concentrations of cystatin C, and given its correlation with the level of NT-proBNP, cystatin C may be objective marker for evaluating heart function [Kim TH, Kim H, Kim IC (2015) The potential of cystatin-C to evaluate the prognosis of acute heart failure: a comparative study. Acute Card Care 17: 72-76; Matana A,

T, Matana

Z (2014) Can the difference in serum concentration of urea and cystatin C be used in diagnosis and prognosis of heart failure? Med Hypotheses 83: 401-403]. According to a study by U. Alehagen et al., The measurement of cystatin C in combination with NT-proBNP is a significant combination of biomarkers for predicting cardiovascular mortality in patients with heart failure [Alehagen U., Dahlstrom U., Lindahl TL Cystatin C and NTproBNP, a powerful combination of biomarkers for predicting cardiovascular mortality in elderly patients with heart failure: results from a 10-year study in primary care. Eur. J. Heart Failure. 2009; 11 (4): 354-360. doi: 10.1093 / eurjhf / hfp024].

The available literature contains only a few studies on the effect of CPT on the biomarkers of immune inflammation, myocardial fibrosis, extracellular cardiac matrix, as well as their relationship to the response to CPT [Cai C, Hua W., Ding L.G., Wang J., Chen K.P., Yang X.W. et al. High sensitivity C-reactive protein and cardiac resynchronization therapy in patients with advanced heart failure. J. Geriatr.Cardiol. 2014; 11: 296-302. DOI: 10.11909 / j.issn. 1671-5411.2014.04.004; Rordorf R., Savastano S., Sanzo A., Spazzolini C, De Amici M., Camporotondo R. et al. Tumor necrosis factor-α predicts response to cardiac resynchronization therapy in patients with chronic heart failure. Circ. J. 2014; 78 (9): 2232-9. PMID: 24954238; Osmancik P., Herman D., Stros P. Linkova H., Vondrak K., Paskova E. Changes and prognostic impact of apoptotic and inflammatory cytokines in patients treated with cardiac resynchronization therapy. 2013; 124 (3): 190-8. DOI: 10.1159 / 000346621; Tarquini R., Guerra C.T., Porciani M.C., Michelucci A., Padeletti M., Riccardi G. et al. Effects of cardiac resynchronization therapy on systemic inflammation and neurohormonal pathways in heart failure. Cardiol. J.2009; 16 (6): 545-52. ISSN 1897-5593; Boriani G., Regoli F., Saporito D., Martignani C, Toselli T., Biffi M. et al. Neurohormones and inflammatory mediators in patients with heart failure undergoing cardiac resynchronization therapy: time courses and prediction response. 2006 Jul; 27 (7): 1776-86. DOI: 10.1016 / j.peptides.2006.02.010, McAloon CJ, Ali D., Hamborg T., Banerjee P., O'Hare P., Randeva H., Osman F. Extracellular cardiac matrix biomarkers in patients with reduced ejection fraction heart failure as predictors of response to cardiac resynchronization therapy: a systematic review. Open heart. 2017.4 (2), e000639].

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A.,

I., Navarro X., Lip G.Y., Moro C. Influence of cardiac resynchronization therapy on indices of inflammation, the prothrombotic state and tissue remodeling in systolic heart failure: a pilot study. Thromb Res. 2011 Oct;128(4):391-4. doi: 10.1016/j.thromres.2011.05.022. Epub 2011 Jun 26; Li M., Zhou Y., Zhou Y., Babu K., Wang Y. Improvement in collagen metabolism after 12

cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Journal of International Medical Research. 2013; 41(1): 200-207. DOI: 10.1177/0300060513475757]. В исследовании Kamioka M. и соавт. исходно и через 6 месяцев после имплантации устройств для СРТ 61 пациенту был исследован уровень СРБ. В группе респондеров смертность, а также, исходный уровень СРБ были достоверно ниже. По результатам исследования уровень СРБ являлся независимым предиктором смерти и неблагоприятного ответа на СРТ [Kamioka М., Suzuki Н., Yamada S., Kamiyama Y., Saitoh S., Takeishi Y. High sensitivity C-reactive protein predicts nonresponders and cardiac deaths in severe heart failure patients after CRT implantation. Int Heart J. 2012;53(5):306-12.]. В исследовании Shinohara Т. и соавт. снижение СРБ также наблюдалось только в группе респондеров [Т Shinohara, N Takahashi, S Saito et al. Effect of cardiac resynchronization therapy on cardiac sympathetic nervous dysfunction and serum C-reactive protein level. Pacing and Clinical Electrophysiology. - 2011. - T. 34. - №. 10. - C. 1225-1230.].A significant decrease in CRP and MMP-9 through the early observation period (3-4 months) was described only in patients with CPT compared with the control group [

F.,

V.,

JG,

D., Ortego M.,

A.,

I., Navarro X., Lip GY, Moro C. Influence of cardiac resynchronization therapy on indices of inflammation, the prothrombotic state and tissue remodeling in systolic heart failure: a pilot study. Thromb res. 2011 Oct; 128 (4): 391-4. doi: 10.1016 / j.thromres.2011.05.0.022. Epub 2011 Jun 26; Li M., Zhou Y., Zhou Y., Babu K., Wang Y. Improvement in collagen metabolism after 12

cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Journal of International Medical Research. 2013; 41 (1): 200-207. DOI: 10.1177 / 0300060513475757]. In a study by Kamioka M. et al. initially and 6 months after implantation of CPT devices, 61 patients were examined for CRP level. In the group of responders, mortality, as well as the initial level of CRP were significantly lower. According to the results of the study, CRP was an independent predictor of death and an adverse response to CPT [Kamioka M., Suzuki N., Yamada S., Kamiyama Y., Saitoh S., Takeishi Y. High sensitivity C-reactive protein predicts nonresponders and cardiac deaths in severe heart failure patients after CRT implantation. Int Heart J. 2012; 53 (5): 306-12.]. In a study by Shinohara, T. et al. a decrease in CRP was also observed only in the group of responders [T Shinohara, N Takahashi, S Saito et al. Effect of cardiac resynchronization therapy on cardiac sympathetic nervous dysfunction and serum C-reactive protein level. Pacing and Clinical Electrophysiology. - 2011. - T. 34. - No. 10. - C. 1225-1230.].

, Oleszczaket K. al. Inflammatory activation following interruption of long-term cardiac resynchronization therapy. Heart and Vessels. - 2012.-C. 1-6.].Rubaj A. et al. 54 patients were examined, all patients initially, after 26-28 weeks after implantation of CPT devices and after the next 2 days of disabling stimulation, an echocardiographic examination was performed, the levels of CRP and other laboratory markers were determined. In the group of non-correspondents during the observation, the dynamics of the studied indicators were not observed. In the group of responders, CRP level significantly decreased against the background of CRT, and its dynamics had an inverse correlation with LVEF. Disabling CPT within 48 hours led to a significant increase in all studied markers, including CRP [Rubaj A.,

, Oleszczaket K. al. Inflammatory activation following interruption of long-term cardiac resynchronization therapy. Heart and Vessels. - 2012.-C. 1-6.].

In a study by Szulik M. et al. comparable baseline levels of MMP-9 were revealed in the group of responders and non-responders, as well as comparable dynamics of MMP-9 after 6 months of observation [Szulik M, Stabryla-Deska J., Boidol J., Lenarczyk R., Kalarus Z., Kukulski T. Echocardiography-based qualification and response assessment to cardiac resynchronization therapy in patients with chronic heart failure. The matrix metalloproteinase-9 substudy. Kardiol Pol. 2011; 69 (10): 1043-51].

I,

В, Macias A, et al. Impact of collagen type I turnover on the long-term response to cardiac resynchronization therapy. Eur Heart J 2008;29:898-906].A study by Garcia-Bolao et al., Which included 59 patients with CHF and CPT, evaluated the prognostic value of extracellular cardiac matrix biomarkers in predicting a response to CPT. According to the results of the study, there was a tendency to higher levels of MMP-9 among respondents on CPT, but the initial level of MMP-9 was not a predictor of the response [

I

B, Macias A, et al. Impact of collagen type I turnover on the long-term response to cardiac resynchronization therapy. Eur Heart J 2008; 29: 898-906].

The association of cystatin C levels with response to CPT was evaluated in The BIOCRT Study. After 6 months, 60% of patients were identified as responders according to the Clinical Composite Score (subjective well-being, decreased functional class of CHF according to NYHA classification and no hospitalization for CHF decompensation). An initial cystatin C level above 1 mg / L was associated with a four-fold increase in the risk of poor response to CPT, as well as an increased risk of significant cardiovascular events over two years [Chatterjee NA, Singh JP, Szymonifka J., Deaflo R. C, Thai WE, Wai B., Min JK, Januzzi JL, Truong QA Incremental value of cystatin With over conventional renal metrics for predicting clinical response and outcomes in cardiac resynchronization therapy: The BIOCRT study. International journal of cardiology. 2016; 205: 43-49. doi: 10.1016 / j.ijcard.2015.12.002].

In a study by Maass A.H. et al. The diagnostic value of a comprehensive model was evaluated, including 11 clinical, 11 electrocardiographic, 4 echocardiographic and 16 laboratory parameters, in predicting the response to CPT [Maass A.N., Vernooy K., Wijers SC, van't Sant J., Cramer MJ, Meine M., Allaart CP, De Lange FJ, Prinzen FW, Gerritse B., Erdtsieck E., Scheerder COS, Hill MRS, Scholten M., Kloosterman M., ter Horst IAH, Voors AA, Vos MA, Rienstra M. Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodeling: results from the Markers and Response to CRT (MARC) study. Europace, 2017. C. euw445.]. All patients (n = 240) were included in the study in accordance with current European and American recommendations for selection for CPT [Epstein A.E., DiMarco J.P., Ellenbogen K.A., Estes N.A., 3rd, Freedman R.A., Gettes L.S. et al. 2012 ACCF / AHA / HRS focused update incorporated into the ACCF / AHA / HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation / American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2013; 127: e283-352; Brignole M., Auricchio A., Baron-Esquivias G., Bordachar P., Boriani G., Breithardt O.A. et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013; 15: 1070-118]. The response to CPT was evaluated 6 months after implantation according to a decrease in the CSJC index by 15% or more. The authors proposed the CAVIAR scale, which includes data on the patient’s age, electrocardiography and echocardiography (mechanical interventricular delay and swing of the apex of the left ventricle). According to the results of multivariate analysis, none of the laboratory indicators was associated with a response to CPT, estimated at 6 months [Maass A.N., Vernooy K., Wijers SC, van't Sant J., Cramer MJ, Meine M., Allaart CP, De Lange FJ, Prinzen FW, Gerritse B., Erdtsieck E., Scheerder COS, Hill MRS, Scholten M., Kloosterman M., ter Horst IAH, Voors AA, Vos MA, Rienstra M. Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: results from the Markers and Response to CRT (MARC) study. Europace, 2017. C. euw445].

The above studies are not numerous, and the results obtained are quite contradictory. An undoubted drawback of the above works is that the assessment of the response to CRT was carried out in strictly defined terms, i.e. 3 or 6 months, which in some cases may not reflect the real dynamics during therapy, since the response to CRT and the timing of its onset are quite individual.

In addition, most of these studies took into account only laboratory parameters and were not complex.

As a prototype, we took one of our previous works, which evaluated the relationship of clinical, laboratory and echocardiographic data with the development of superresponse on CPT, evaluated during the entire observation period [Kuznetsov VA, Soldatova AM, Krinochkin DV, Enina T.N., Petelina T.I., Rychkov A.Yu. A method for predicting a super response to cardiac resynchronization therapy in patients with chronic heart failure. Patent No. 2623487]. A model was proposed based on data on the patient's age, duration of the period of aortic prediction according to the results of echocardiography and the level of NT-proBNP, which allows to predict the development of a super response with a specificity of 71.9% and a sensitivity of 82.1%. The method for predicting a super response is complex and includes clinical, echocardiographic, and laboratory parameters, however, the disadvantage of the prototype is that the model provides for the assessment of indicators of mechanical dyssynchrony, which depend on the experience of the researcher and, as you know, are not included in the list of generally accepted criteria for examining patients with heart failure with selection for CPT, and require additional time costs. In addition, the study on the basis of which the model was created included patients with a width of QRS <130 ms in the presence of mechanical dissynchronization criteria, which, according to current recommendations for selection for CPT, are not candidates for implantation of devices for CPT. It should be noted that the prediction of the super response does not allow making decisions about the need for implantation, since it does not allow to separate responders and non-responders, which is of fundamental importance for a practical cardiologist when selecting patients.

The proposed method for predicting the response to CPT is characterized in that the technique is based on generally accepted criteria for the selection of patients and from echocardiographic parameters includes an assessment of the ejection fraction of the left ventricle. Also, a method for predicting a response to CPT includes laboratory indicators that are independent of the experience and qualifications of the researcher. The proposed method for predicting a response to CRT does not require additional time costs when examining patients. The proposed method allows to predict the development of the response to CPT, in other words, to exclude patients whose CPT will be ineffective, thereby improving the quality of selection and reduce the number of non-responders.

The purpose of this study is to identify signs associated with the development of a response in patients with heart failure directed to the implantation of devices for CRT; create a model using which it would be possible to predict the development of the response at the preoperative stage; check the resulting model. Ultimately, increase the effectiveness of treatment of patients with severe CHF.

The essence of our proposed method is the use of echocardiography - a widespread, harmless and affordable method and laboratory results of the levels of CRP, MMP-9, cystitis C. The proposed method for predicting a super response to CPT was developed as follows. From the number of patients included in the "Register of Cardiac Resynchronization Therapy Operations", © State Registration Certificate for Database No. 2010620077, was registered in the Database Registry on February 1, 2010, which underwent a comprehensive clinical and instrumental examination at the Tyumen Cardiology Center from 2005 to 2015, patients with unstable angina with ST and T changes on the electrocardiogram, recently suffered acute myocardial infarction or acute cerebrovascular accident (<6 months) were excluded ), the presence of hemodynamically significant stenosis and occlusion, a multivascular lesion of the coronary arteries without effective myocardial revascularization, patients with severe somatic pathology whose prognostic life expectancy did not exceed 1 year, patients with no current criteria for implantation, as well as patients with the inability to full dynamic observation. A complete prospective observation was performed in 32 patients referred for CPT.

All patients initially, 1, 3, 6 months and every subsequent 6 months after implantation of devices for CPT underwent clinical, echocardiographic and laboratory examination with determination of the levels of CRP, MMP-9, cystatin C. The average follow-up was 34.3 ± 11, 3 months. Echocardiography was performed using a stationary ultrasound device Philips IE-33 - USA, multi-frequency sensors 2.5-5.0 MHz. Standard echocardiographic sections were used: parasternally along the long and short axes of the left ventricle, apical two-, four-, five-chamber positions and along the long axis of the left ventricle. The study was performed in the patient's position on the left side with a raised head end. Synchronously with echocardiography, one ECG lead was automatically recorded. Echocardiographic syndromes were diagnosed according to standard criteria [N. Schiller, M. Osipov. Clinical echocardiography. Practice 2005, 344; Recommendations for quantifying the structures and functions of the heart chambers Russian Journal of Cardiology. 2012, 3 (95)]. The size of the right ventricle was measured in the parasternal position along the long and short axes in diastole at the level of the top of the R wave of the ECG, or at the point of maximum separation of the walls of the ventricle. The size of the LP was determined in systole, subject to the direction of the cursor strictly perpendicular to its rear wall. Pulmonary systolic pressure (SLA) was calculated using the modified Bernoulli equation based on the maximum tricuspid regurgitation rate measured by continuous wave doppler doppler echocardiography. The pressure in the right atrium was determined by the size of the respiratory index of the inferior vena cava.

LVEF was determined by calculating LV volumes using the disc technique (modified Simpson algorithm) in two-dimensional mode from apical access at the positions of two and four cameras.

The diagnosis of heart failure was made on the basis of the National recommendations for the diagnosis and treatment of heart failure [V.Yu. Mareev, F.T. Ageev, G.P. Arutyunov et al. National Recommendations of ASCH, RKO and RNMOT for the diagnosis and treatment of chronic heart failure (fourth revision). Heart failure. - T. 14 - No. 7 (81). 2013].

Echocardiography evaluated the response to CPT. Patients were considered responders with a decrease in LVLD by 15% or more compared to baseline during the entire observation period, with a decrease in LVLD of less than 15%, patients were considered non-responders, in other words, when evaluating the response, the period of the highest decrease in LVLD was taken into account, subject to further stabilization of functional indicators.

Plasma levels of MMP-9 were studied by solid-phase chemiluminescent enzyme-linked immunosorbent assay (sandwich method) on an IMMULITE 1000 analyzer (Siemens Diagnostics, USA). The highly sensitive CRP fraction in blood serum was determined by the immunoturbidimetric method using C-REACTIVE PROTEIN hs analytical kits (BioSystems, Spain) on a Clima MC-15 analyzer (Spain). Quantitative determination of cystatin C in serum was carried out by the sandwich method using Human Cystatin C Elisa analytical kits (BioVendor, Czech Republic). The optical density was measured using a Stat Fax 4200 reader.

The main criteria for selecting patients were:

1. CHF II-IV FC according to NYHA classification;

2. LVEF ± 35%;

3. The width of the QRS complex is more than 150 m / s and / or the presence of a blockade of the left bundle branch block with a QRS width> 130 ms;

4. Optimal drug therapy over the past three months. Statistical analysis was performed using the SPSS 21 software package (SPSS Inc., Chicago, IL, USA). The normality of the distribution was evaluated by the Kolmogorov-Smirnov method. For a normal distribution, the results are presented in the form M ± SD, where M is the average value, sd is the standard deviation, and for an abnormal one, the median and interquartile range (Me [25; 75]). When analyzing qualitative data in unrelated groups, the Chi-square test was used. To compare the quantitative data in unrelated groups with their normal distribution, the Student t-test was used, with abnormal - the Mann-Whitney criterion. Binary logistic regression was used to identify response predictors. Differences were considered significant at p <0.05.

Having examined the features of the clinical and functional parameters of patients, we set ourselves the goal of selecting from the set of considered signs only the essential ones, that is, having diagnostic value in predicting the response to CRT. We did not find data on the use of the results of combined laboratory and echocardiographic examinations to predict the best response to CPT in the available literature.

To solve this problem, we used multivariate analysis - binary logistic regression. The initial set of variables included signs that reliably distinguished groups of patients. These included: the age of the examined patients, LVEF, systolic pressure in the pulmonary artery, the size of the right ventricle, MMP-9, CRP, cystatin C, NT-proBNP. As a result of the analysis, the essential features characterizing the invention were selected, a model with four variables was created.

The technical result is expressed by the formula for calculating the value of the function F:

F = 3.231 + 0.344 × EF-3.479 × CYSTATIN-0.039 × MMP9-0.638 × CRB,

where the variable EF is the ejection fraction of the left ventricle in%;

CYSTATIN variable - cystatin C level in ng / l;

MMP9 variable - matrix metalloproteinase level - 9 in ng / l;

CRB variable - C-reactive protein level in ng / l;

further, the response to cardiac resynchronization therapy (P) is predicted: P = 1 / (1 + e ^(-F) ), with a value of P less than 0.696, membership in the group of non-responders is determined, and with a value of P greater than or equal to 0.696, the group of responders and predict a response to cardiac resynchronization therapy.

The specificity of this model was 92.9%, and the sensitivity was 83.3%. The area under the ROC curve - for our model it was 0.952 (p <0.001), which corresponds to a very good quality model.

Thus, the proposed method consists in the following: after a clinical examination of a patient planned for an operation to implant a device for CPT, he undergoes an echocardiographic examination with an assessment of LVEF and a laboratory examination with an assessment of the levels of cystatin C, MMP-9, CRP. Further, using the formula obtained by us, it is possible to fairly accurately determine its belonging to a group of patients with a planned response to cardiac resynchronization therapy, that is, pronounced reverse remodeling of the left ventricle.

The essential features characterizing the invention and distinguishing the claimed technical solution from the prototype, showed in the claimed combination of new properties that are not explicitly derived from the prior art and are not obvious to a specialist.

The result once again highly reliably confirms the prognostic value of the main key mechanisms of development and progression of heart failure: immune inflammation, fibrosis and renal dysfunction, which emphasizes the need for a comprehensive study of a patient with heart failure, which is a candidate for implantation of a device for CPT.

An identical set of features was not found in the patent and medical literature of this and related fields of medicine.

The proposed method can be used in practical health care, does not require special conditions for carrying out, economical in time, easy to operate. The CPT method is expensive, and the use of the model we offer will allow for a more thorough selection for this type of therapy with the ability to predict the response, which will reduce the cost of its implementation and ultimately lead to budget savings.

Based on the foregoing, the proposed invention should be considered relevant to the conditions of patentability "novelty", "inventive step", "industrial applicability".

CLINICAL EXAMPLE No. 1

Patient K., 64 years old, after self-treatment, was admitted to the Coronary Insufficiency Department No. 3 of the Branch of the Tyumen Cardiology Center Research Institute of Cardiology with complaints of shortness of breath, pressing pains in the chest area when walking at a moderate pace up to 50 meters, aching pain in the left half of the chest without a clear connection with physical and emotional stress. Over the past year, he has noted complaints of an increase in pressure up to 180/120 mm Hg. Deterioration over the past three months. Permanent prem drugs were not carried out.

Initially according to electrocardiography: ventricular extrasystole, blockade of the left bundle branch block, QRS 160 ms.

According to echocardiography: Aortic atherosclerosis, sclerosis of the valves of the aortic valve with slight regurgitation. Dilation of the left parts with signs of moderate mitral regurgitation. Against the background of diffuse hypokinesis, a moderate decrease in the contractile function of the heart (LVEF 35%), CSOL 120 ml. Signs of minor pulmonary hypertension. Echoes of intraventricular dyssynchrony.

With selective coronary angiography (Diagnost ARC A angiographic complex, Holland), according to the Judkins method, there are no angiographic data for hemodynamically significant stenotic lesions of the coronary arteries. The distal coronary arteries are convoluted.

The patient was discharged with a diagnosis of Arterial hypertension stage III, degree 3, risk 4 (very high). Complete blockade of the left bundle branch block. Rhythm disturbance as a type of frequent ventricular extrasystole. CHF IIA FC III (NYHA).

The patient was prescribed drug therapy for heart failure, scheduled hospitalization after three months was prescribed.

Three months later, with repeated hospitalization, the patient complains of shortness of breath with minimal physical exertion, edema of the lower extremities, severe weakness, fatigue, periodically pressing pains in the left half of the chest with radiation to the left shoulder blade, arising without connection with physical activity and stopping on their own.

According to electrocardiography: blockade of the left bundle branch block, QRS 162 ms.

According to echocardiography: Aortic atherosclerosis, sclerosis of the valves of the aortic valve with slight regurgitation. Dilation of the left parts with signs of moderate mitral regurgitation. Against the background of diffuse hypokinesis, a moderate decrease in the pumping function of the heart (LVEF 35%), CSOL 120 ml. Signs of minor pulmonary hypertension. Echoes of intraventricular dyssynchrony.

Laboratory study: The initial level of cystatin C is 0.21 ng / l, the level of MMP-9 is 62.45 ng / l, the level of CRP is 4.09 ng / l.

Using the available data, we first calculated the value of the function F:

F = 3.231 + 0.344 × EF - 3.499 × CYSTATIN - 0.039 × MMP9 - 0.638 × CRB,

= 3.231 + 0.344 × 35 - 3.499 × 0.21 - 0.039 × 62.45 - 0.638 × 4.09 = 8.134

Then calculated the probability value P:

P = 1 / (1 + e ^(-F) ) = 1 / (1 + 2.718 ^8.134 ) = 0.999

The obtained P value of 0.999 allowed the patient at the preoperative stage, in addition to generally accepted criteria, with a high probability to suggest the development of a response to CPT.

Taking into account clinical and medical data, progression of CHF symptoms, ineffectiveness of drug therapy and high risk, the patient was implanted with a permanent biventricular pacemaker - Consulta Medtronic with endocardial electrodes. In dynamics, the patient notes a subjective improvement in well-being within a week after implantation.

Discharged with a diagnosis of Arterial hypertension stage III, grade 3, risk 4 (very high). Complete blockade of the left bundle branch block. Ventricular extrasystole, polymorphic, steam room. Permanent biventricular ECS Consulta Medtronic with endocardial electrodes. CHF IIB with attacks of cardiac asthma. FC IV (NYHA). Dyslipidemia.

According to echocardiography:

- after 6 months, positive dynamics in the form of a decrease in volumes (CSLD 105 ml), LVEF up to 43%, FC II according to NYHA;

- after 12 months, positive dynamics, CSOL of 85 ml, LVEF up to 45%, FC II according to NYHA;

- after 18 months - LVEF 49%, in the dynamics of normalization of the size of the left parts of the heart, LVSC 55 ml, FC II NYHA.

- after 30 months - LVEF 55%, CSLV 49 ml, FC I according to NYHA.

Thus, the proposed method allows with high accuracy among patients planning to implant devices for CPT to predict the development of a response in a patient, which ensures effective selection of patients for implantation, as well as reducing the number of non-responders.

CLINICAL EXAMPLE No. 2

Patient Ch., 37 years old, was observed at the Tyumen Cardiology Research Center since 2005 with a diagnosis of IHD. Postinfarction (2005) cardiosclerosis. Postinfarction apical aneurysm of the left ventricle. Ventricular fibrillation. Paroxysms of unstable ventricular tachycardia. CHF IIA. FCS (NYHA). Dyslipidemia.

Coronary angiography was performed twice (from 2006 and 2009): the arteries in the distal parts are thinned, there is no data for stenotic lesions of the arteries. In 2009, the patient was implanted with a permanent IVR with the function of a carduverter-defibrillator Virtuoso DR Medtronic with endocardial electrodes Medtronic.

In October 2011, he was hospitalized in the surgical treatment department for complex cardiac arrhythmias and cardiac pacing, a branch of the Tyumen Cardiology Center Research Institute of Cardiology, with complaints of shortness of breath of mixed nature during exertion (rise to the 2nd floor), periodic pains of a pressing nature in the area, palpitations general weakness. It has been deteriorating since July 2011. 2 episodes of unstable ventricular tachycardia (5-65 complexes) were recorded on the arrhythmia counter.

According to electrocardiography, an QRS extension of up to 160 ms, a blockade of the left bundle branch block were recorded.

According to the results of echocardiography: increased echogenicity of the walls of the aorta. Extensive circular cicatricial changes in the left ventricular myocardium with signs of postinfarction apical left ventricular aneurysm. Severe dilatation of the left heart with signs of moderate mitral regurgitation. Decreased global LV contractile function (LVEF 31%). Elements of the probe electrode in the right heart. Signs of intra- and interventricular dysynchrony.

Laboratory study: cystatin C level - 0.41 ng / l, MMP-9 level - 318.3 ng / l, CRP level - 4.49 ng / l.

Using the available data, we first calculated the value of the function F:

F = 3,231 + 0,344 × EF - 3,479 × CYSTATIN - 0,039 × MMP9 - 0,638 × CRB, = 3,231 + 0,344 × 31 - 3,479 x 0,41 - 0,039 × 318,3 - 0,638 × 4,49 = -2,809

Then calculated the probability value P:

P = 1 / (1 + e ^(-F) ) = 1 / (1 + 2.718 ^-2.809 ) = 0.057

The obtained P value of 0.078 allowed the patient to suggest the absence of a response to CRT if there are classical criteria for implantation (III FC CHF according to NYHA, LVEF 31%, QRS 160 ms, BLNPG).

The patient was consulted in absentia with a senior research fellow of the department of HLSNRS Research Institute named after Meshalkina Romanov A.B. It is recommended to replace the cardioverter-defibrillator with CPT-D. The patient was implanted with a permanent biventricular IVR with the function of a cardioverter - defibrillator - CONTAK RENEWAL Boston Scientific.

Discharged with a diagnosis of IHD. Postinfarction cardiosclerosis (2005). Ventricular fibrillation, ventricular tachycardia. Permanent biventricular IVR with cardioverter-defibrillator function - CONTAK RENEWAL Boston Scientific (2011) with Medtronic endocardial electrodes (2009), left ventricular electrode (2011). CHF IIA FC III.

According to echocardiography:

- after 6 months, the dimensions of the cardiac cavities without significant dynamics, CSOL 189 ml, LVEF up to 33%, FC III according to NYHA;

- after 12 months, the dynamics of an increase in heart cavities, CSLD 239 ml, LVEF up to 31%, FC III according to NYHA; The optimization of the operation parameters of the CPT system was carried out: AV delay -120 ms, VV delay - 30 ms;

- after 18 months - LVEF 33%, the size of the cardiac cavities without significant dynamics, CSOL 230 ml, FC III NYHA. The optimization of the parameters of the CPT system was carried out: AV delay -120 ms, VV delay - 0 ms;

- after 30 months - LVEF 30%, without significant dynamics, CSLV 232 ml, FC III according to NYHA.

Thus, the patient at the preoperative stage was predicted to have no response to CRT. However, taking into account the available criteria for implantation, a biventricular pacemaker was implanted into the patient, and no positive effect was obtained.

Claims (7)

A method for predicting a response to cardiac resynchronization therapy in patients with chronic heart failure, including echocardiography, characterized in that the ejection fraction of the left ventricle is determined in% during echocardiography, in addition, the patient determines the level of cystatin C in ng / l, matrix metalloproteinase in ng / l, C-reactive protein in ng / l in the blood; based on the data obtained, determine the value of the function F: F = 3.231 + 0.344 × EF-3.479 × CYSTATIN-0.039 × MMP9-0.638 × CRB, where the variable EF is the ejection fraction of the left ventricle in%; CYSTATIN variable - cystatin C level in ng / l; MMP9 variable - matrix metalloproteinase level - 9 in ng / l; CRB variable - C-reactive protein level in ng / l, further, the response to cardiac resynchronization therapy (P) is predicted: P = 1 / (1 + e ^(-F) ), with a value of P less than 0.696, membership in the group of non-responders is determined, and with a value of P greater than or equal to 0.696, it belongs to the group of responders and predict a response to cardiac resynchronization therapy.