EA035661B1 - Method for predicting cardiovascular complications of early postoperative period in patients with ischemic heart disease with initially reduced left ventricle contractility after open heart surgery - Google Patents

Abstract

The invention relates to medicine, in particular, to cardiosurgery and laboratory diagnostics.. In accordance with the invention, a method for predicting cardiovascular complications of early postoperative period in patients with ischemic heart disease with initially reduced left ventricle contractility after open heart surgery is described, which consists in the following: the patient undergoes preoperative echocardiographic study to confirm the presence of reduced heart contractility and to determine the severity of functional ischemic mitral insufficiency, then the level of myocardial fibrosis biomarker sST2 in blood is assessed and compared with a reference threshold value, and at a level of sST2 lower than 45 ng/mL, a low risk of complicated postoperative period is established, and at a level of sST2 higher than 45 ng/mL, a high risk of low cardiac output syndrome developing in the postoperative period after open heart surgery is established. The technical result achieved by the invention is to increase accuracy, reliability and quality of predicting complicated postoperative period in patients with ischemic heart disease with reduced heart contractility after open heart surgery.

Description

The invention relates to medicine, namely to cardiac surgery, laboratory diagnostics.

The assessment of operational risk in adults undergoing open heart surgery remains a major challenge, especially among high-risk patients. The exact stratification of the risk of surgical treatment is of great importance in daily cardiac surgery practice. It allows not only to assess the actual risk of surgery, but also serves as an additional tool in the selection of patients for a particular treatment method. An accurate assessment of the risk of open heart surgery also allows you to select patients who can get the most out of the treatment performed and reduce the risk of complications.

In European countries, the EuroSCORE II scale is most often used to assess the risk of an operation, in the USA - the STS risk model scale. However, the Euroscore scale allows to determine only the risk of postoperative death in cardiac surgery patients [1]. The STS risk calculator makes it possible to assess not only the risk of death, but also the likelihood of postoperative complications, and also to suggest a longer postoperative period. However, when calculating the predictive indicators of the STS risk model, an assessment of the risk of developing small cardiac output syndrome is also not provided.

The clinical protocol for the diagnosis and treatment of diseases complicated by heart failure [2] involves the determination of the level of brain natriuretic hormone (BNP) * or its N-terminal precursor (NT-proBNP) in order to diagnose and assess the prognosis of patients with chronic heart failure (CHF). The joint recommendations of the American College of Cardiology and the American Heart Association (ACC / AHA) for 2017 indicate the possibility of using other biomacrers (such as biomarkers of myocardial fibrosis sST-2, galectin-3, high-sensitivity troponin, etc.) to clarify the prognosis and stratification the risk of patients with CHF [3]. Several randomized controlled trials have been conducted around the world to study the possibility of CHF therapy under the control of various biomarkers (primarily the natriuritic peptide family) [4]. And in the application US 20150268251 A1 [5] describes the possibility of using various biomarkers to change the prescribed drugs and their dosages for the treatment of patients with CHF.

sST2 (stimulating growth factor expressed by gene 2, also known as IL1RL1) is a member of the interleukin-1 (IL-1) receptor family. sST2 simultaneously reflects the state of inflammation, fibrosis and myocardial stress. The sST-2 Presage ST2 assay laboratory diagnostic kits manufactured by Critical Diagnostics LTD are approved by the Food and Drug Administration (USA) and are registered in the Republic of Belarus. The study of the level of this biomarker is shown as an addition to the clinical diagnosis of patients in order to assess the prognosis in patients with CHF [6].

A known method for predicting the risk of cardiovascular complications in a patient with Q-myocardial infarction in the early postoperative period of coronary artery bypass grafting [7], which consists in the fact that the patient at the preoperative stage undergo an echocardiographic study and biochemical blood test, while determining the following prognosis criteria: myocardial stress in systole MSc in g / cm ² , index of local myocardial contractility of ILSM in points, blood content of brain natriuretic peptide BNP in pg / ml, troponin I Tn I in ng / ml and von Willebrand factor FrVl in percentage, prognosis criteria are estimated in points in accordance with the table of descriptions or equated to 0 points if their values are less than those indicated in the table, the points obtained are summed up and predict the risk of developing cardiovascular complications as low with a total of 0-2 points, or as average with a total of 3-5 points, or as high with a total score of 6 or more.

There is also known a method for predicting the likelihood of acute heart failure in a patient with unstable angina pectoris in the early postoperative period of coronary bypass grafting [8], which consists in the fact that the patient in the preoperative period undergo an echocardiographic study, and determine the index of local myocardial contractility of the ILCM in points and end-systolic CSI index in ml / m ² , daily monitoring of the electrocardiogram is carried out, and the daily myocardial ischemia of the CIM in min / day is determined, the logit p value is calculated according to the formula logit p = -17.128 + 2.246 ILSM - 0.012CIM - 0.079CSI, and predicting the likelihood of acute heart failure in a patient with unstable angina pectoris in the early postoperative period of coronary artery bypass grafting by the value of the probability p, which is calculated by the formula ^P “ _{1 + e} - ^ ₽

There is also a known method for assessing the burden of the risk of cardiac surgery [9], which consists in the fact that a patient whose risk indicator is determined in points on the EuroSCORE scale is carried out two 6-minute walk tests with an interval of 20-30 minutes with ECG holter monitoring, the values of the lengths of the covered distances, the lengths of the distances covered until the moment of the maximum depression of the ST segment, and the indicators of heart rate variability, calculate the ratio of the corresponding 1,035661 values of the first and second tests, and when the value of the ratio of the lengths of the covered distances is less than 1, they conclude that the risk is aggravated reserve of myocardial function, if the value of the ratio of the lengths of the distances covered until the moment of maximum depression of the ST segment is less than 1 - about the aggravation of the risk by depletion of the reserve of coronary circulation, and if the value of the ratio of heart rate variability indicators is less than 1 - about the aggravation of the risk by depletion of the neurohumoral reserve.

However, the known methods have a number of the following disadvantages and limitations in application:

1) the above methods (Euroscore II and STS risk-score calculator) are designed to assess the risk of mainly postoperative mortality, regardless of the etiology of the disease in patients and do not take into account the development of small cardiac output syndrome;

2) the Euroscore I point scale is not currently applied,

3) most of the parameters that form the basis of risk assessment according to the Euroscore II scale are based on the definition of qualitative rather than quantitative characteristics,

4) the method proposed for persons with acute forms of coronary artery disease (Q-myocardial infarction or unstable angina pectoris), which are significantly different in clinical course and outcomes of the disease, does not take into account the nature of cardiovascular complications themselves and cannot be transferred to patients with chronic forms of ischemic heart disease ,

5) this method also lacks laboratory biomarkers of myocardial fibrosis (sST-2), which assesses the state of the affected myocardium and plays an important role in the development of postoperative cardiovascular complications in patients with reduced left ventricular contractility,

6) in the methods describing the possibility of using therapy under the control of the level of biomarkers and stratification of the risk of the course of CHF, there is no indication of a connection with cardiac surgery.

The prior art has not found a method for predicting the risk of developing a complicated course of the early postoperative period from the perspective of hemodynamic disturbances in patients with reduced left ventricular contractile function after performing isolated coronary artery bypass grafting or in combination with correction of functional ischemic mitral insufficiency.

The technical result of the invention is to improve the accuracy, reliability and quality of the prognosis of the complicated course of the postoperative period in patients with ischemic heart disease with reduced contractile function of the heart after open heart surgery.

The specified technical result is achieved by the claimed method for predicting cardiovascular complications of the early postoperative period in patients with ischemic heart disease with an initially reduced contractile function of the left ventricle after open heart surgery, which consists in the fact that the patient in the preoperative period undergo an echocardiographic study, which confirms the presence of a reduced fraction left ventricular ejection is less than 40%, then the blood level of the biomarker of myocardial fibrosis sST2 is assessed, the value of the sST2 biomarker is compared with the reference threshold value, and when the sST2 level is less than 45 ng / ml, a low risk of developing cardiovascular complications due to small cardiac output syndrome is established , and when the sST2 level is more than 45 ng / ml, it is concluded that there is a high risk of developing cardiovascular complications in the early postoperative period due to the syndrome of small cardiac output after surgery. open heart.

In accordance with the invention, a patient with ischemic heart disease (IHD) who is planned to undergo isolated coronary artery bypass grafting (CABG) or in combination with correction of functional ischemic mitral regurgitation, at the preoperative stage to predict a complicated postoperative period (small cardiac output syndrome), instrumental studies are performed - echocardiography (Echo-KG) and laboratory examination of a blood count characterizing myocardial fibrosis (sST-2).

The predictive value of the sST-2 biomarker of myocardial fibrosis was revealed by comparing 29 parameters (clinical, instrumental, and laboratory) using logistic regression analysis. The study was carried out in patients with coronary artery disease with reduced myocardial contractility (biplane ejection fraction of the left ventricle according to the modified Simpson method less than 40%) who underwent isolated coronary artery bypass grafting or CABG in combination with correction of functional ischemic mitral insufficiency.

In the context of this method, the determination of the biomarker of myocardial fibrosis sST2 is carried out in plasma or serum by the method of enzyme-linked immunosorbent assay (ELISA) in the form of a well microplate by The Presage® ST2 Assay test system, Critical Diagnostics LTD.

Complicated postoperative period from the standpoint of hemodynamic disturbances and the development of small cardiac output syndrome, in this method of predicting it, is defined as a combined point. Namely, this concept includes: 1) hospital mortality due to cardiac causes (cardiogenic shock, acute cardiovascular failure, myocardial infarction, progression

- 2 035661

CHF in the postoperative period, leading to mortality); 2) the use of circulatory support systems in the early postoperative period (left ventricular bypass, ECMO); 3) the use of intra-aortic balloon counterpulsation; 4) cardiotonic therapy extended for more than 24 hours after surgery.

Reduced contractile function of the heart in the context of this prediction method was determined according to the data of instrumental diagnostics. A patient with coronary artery disease with reduced cardiac contractile function was determined if the left ventricular ejection fraction (LVEF) of the heart was less than 40%, determined from biplane echocardiography using the modified Simpson method.

In the context of this prediction method, open heart surgery implies performing a coronary artery bypass grafting in a patient with coronary artery disease in isolation or in combination with correction of functional ischemic mitral insufficiency under cardiopulmonary bypass.

In the context of this method, the term reference threshold value denotes a value that allows a patient to be identified in one of the risk groups for a complicated postoperative course after an isolated coronary artery bypass grafting operation or CABG in combination with correction of functional ischemic mitral insufficiency. Thus, the obtained reference value is the threshold for dividing patients into different groups: complicated and uncomplicated postoperative period. This value was obtained when assessing the results of preoperative study of the level of the sST-2 biomarker and the course of the postoperative period in 150 patients after cardiac surgery. Basic echocardiographic data reflecting impaired cardiac contractility and expansion of its cavity, and the parameters of the biomarker profile were selected to build a prognostic model of the complicated (in terms of hemodynamic disorders) course of the postoperative period in patients with coronary artery disease. The threshold value of the independent predictor sST-2, identified during the analysis of preoperative data, its diagnostic and prognostic significance for predicting a complicated (in terms of hemodynamic disorders) course of the postoperative period were determined using operating characteristics curves (ROC curves). ROC curves are a graph of all pairs of sensitivity-versus-specificity for a continuous variation series of all possible threshold values of the level of sST-2 of the operated patients obtained as a result of the study. The y-axis of this graph displays the sensitivity, namely the proportion of true positive cases. The X-axis is the parameter 1-specificity, namely the proportion of false positives. The threshold value of the parameter is selected taking into account the balance requirement and the maximum total sensitivity and specificity of the model.

For statistical comparison of diagnostic models, the following operational characteristics were selected: 1) sensitivity; 2) specificity; 3) positive predictive value; 4) negative predictive value; 5) ratio of likelihood. Sensitivity (HR) is the proportion of patients with correctly recognized cases. Specificity (C) - the proportion of patients with correctly recognized non-cases. A positive predictive value (PC +) is the proportion of patients with a positive diagnostic test result who have a complication. Negative predictive value (PC -) is the proportion of patients with a negative diagnostic test result who do not have a postoperative complication. Likelihood ratio (LR) for a positive result = sensitivity / (1-specificity).

The reference threshold value of the biomarker of myocardial fibrosis sST-2 as a predictor of the development of small cardiac output syndrome was 45 mg / ml. So, at the sST-2 level of more than 45 mg / ml, a complicated (in terms of hemodynamic disorders) course of the postoperative period can be predicted with the model sensitivity of 81.8% and specificity of 93.8%. The positive predictive value for the defined cut-off value was 89.5%. So, when the preoperative threshold level of sST2 is exceeded 45 ng / ml, the odds ratio (OR) of the complicated course of the postoperative period is 5.345 (95% CI 3.6-9.78, p = 0.01).

In a patient with coronary artery disease who is to undergo surgery, at the stage of preoperative preparation, echocardiographic examination is performed on a digital ultrasound machine of a cardiac profile using a transducer with a scanning frequency of 3.5 MHz according to the standard technique. Biplanovo using a modified Simpson method will determine the left ventricular ejection fraction, as well as assess the degree of mitral valve insufficiency. When an indication for performing isolated coronary artery bypass grafting or CABG surgery in combination with the correction of functional ischemic mitral insufficiency, in addition to a detected LVEF of less than 40%, venous blood is taken for laboratory studies and (in plasma or serum by enzyme immunoassay) the sST2 content is determined. Evaluate the result of the test obtained with the proposed reference threshold value of the independent prediction factor. If the sST2 level is less than 45 ng / ml, the patient is assigned to the low-risk group. The risk of developing a postoperative period, complicated from the standpoint of hemodynamic disturbances, does not exceed that in other groups of prooperative patients. When the sST2 level is more than 45 ng / ml, the patient is distributed in

- 3 035661 high risk groups. The risk of developing postoperative hemodynamic disorders complicated from the standpoint of hemodynamic disturbances (hospital mortality due to cardiac causes, use of circulatory support systems in the early postoperative period, use of intra-aortic balloon counterpulsation or cardiotonic therapy prolonged for more than 24 hours after surgery) is high with the ratio of the chances of developing small cardiac output syndrome in the postoperative period. the period of the field of open heart surgery from 3.6 to 9.78, namely 5.345.

The developed method makes it possible to accurately assess the likelihood of developing small cardiac output syndrome in the early postoperative period after isolated coronary artery bypass grafting (CABG) or in combination with the correction of mitral insufficiency in patients with initially reduced myocardial contractility. This allows you to draw up an individual plan for preoperative preparation and determine the tactics of treating heart failure in these patients in the early postoperative period.

The claimed method is confirmed by the following examples of specific implementation.

Example 1.

Patient S.E.V. was admitted for planned surgical treatment with a diagnosis of coronary artery disease. Postinfarction cardiosclerosis with clinical features of chronic heart failure FC III (NYHA classification). The patient was examined according to the proposed method. Thus, LVEF according to echocardiography was 33%, there was a pronounced expansion of the left ventricular cavity with an end-diastolic diameter of 70 mm, an end-diastolic volume of 256 ml and functional ischemic mitral insufficiency of grade 3. In accordance with the developed method, the patient was determined the level of sST2, which was 17.29 ng / mg. The risk of developing small cardiac output syndrome during the operation period was assessed as low.

The patient underwent open heart surgery: coronary artery bypass grafting combined with mitral valve annuloplasty. The patient had no hemodynamic complications in the early postoperative period; he was safely transferred to the general cardiac surgery department on the 1st day after the operation.

A favorable prognosis for the course of the early postoperative period was justified. Thus, a patient with a low risk of complications was identified, in whom, despite signs of systolic dysfunction of the LV myocardium and signs of chronic heart failure preoperatively, in the early postoperative period there were no symptoms of small cardiac output syndrome. Thus, the increase in the accuracy, reliability and quality of the forecast was confirmed. This allowed him to reduce additional research, he was earlier transferred from the cardiac intensive care unit and earlier discharged from the hospital with an improvement in his condition, which led to significant savings in financial costs of treatment.

Example 2.

Patient T.E.G. also entered the clinic for cardiac surgery with a diagnosis of coronary artery disease. Postinfarction cardiosclerosis with signs of chronic heart failure FC III (NYHA classification). The patient was examined according to the proposed method. The following parameters were obtained: LVEF according to echocardiography was 28%, end-diastolic diameter of the left ventricle was 63 mm, end-diastolic volume was 178 ml, and functional ischemic mitral insufficiency of grade 3 was confirmed. In accordance with the developed method, the patient was determined the level of sST2, which was 71.65 ng / mg. The risk of developing a postoperative period complicated from the position of hemodynamic disturbances (hospital mortality due to cardiac causes, use of circulatory support systems in the early postoperative period, use of intra-aortic balloon counterpulsation or prolonged more than 24 hours after surgery, cardiotonic therapy) in this patient was assessed as high.

The patient underwent coronary artery bypass grafting with mitral valve annuloplasty. In the early postoperative period, the patient developed a small cardiac output syndrome, which required the connection of the intra-aortic balloon counterpulsation system and prolonged cardiotonic therapy for more than 72 hours. The unfavorable prognosis of the early postoperative period was confirmed.

Thus, the developed prognostic model is important for the individual prognosis of the development of hemodynamic disorders that require additional medical treatment, the use of mechanical support methods in some cases, which is reflected in the cost of treatment. Evaluation of the risk of developing small cardiac output syndrome by the developed method allows in each case to identify the features of the complicated course of the early postoperative period, as well as to develop an individualized program for its prevention and treatment already at the preoperative stage.

Sources of information

1. Performance of the European System for Cardiac Operative Risk Evaluation II: a meta-analysis of 22 studies involving 145,592 cardiac surgery procedures. / Guida P, Mastro F, Scrascia G, et al. // J Thorac Cardio- 4 035661 vasc Surg. - 2014. - Dec; 148 (6). - 3049-57.

2. Resolution of the Ministry of Health of the Republic of Belarus No. 59 of June 06, 2017

3..2017 ACC / AHA / HFSA Focused Update of the 2013 ACCF / AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology / American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. / Yancy CW, Jessup M, Bozkurt B. et al. // Circulation. - 2017.- Aug 8; 136 (6) .- e137-e161.

4. The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis, prognosis and management. / Ibrahim N, Januzzi JL // Expert Rev. Cardiovasc. Ther. -2015-13 (9) - p.1017-30.

5. US 20150268251 A1, publ. 24.09.2015.

6. Soluble ST2-analytical considerations. / Mueller T, Jaffe AS // Am J Cardiol-2015.Apr 2; 115 (7 Suppl). 8B-21B.

7. Patent of the Republic of Belarus No. 17666, publ. 30.10.2013.

8. Patent of the Republic of Belarus No. 17660, publ. 30.10.2013.

9. Patent of the Republic of Belarus No. 14981, publ. 30.10.2011.

Claims (1)

CLAIM A method for predicting cardiovascular complications in the early postoperative period in patients with ischemic heart disease with an initially reduced left ventricular contractile function after open heart surgery, consisting in the fact that the patient in the preoperative period undergo an echocardiographic study, which confirms the presence of a reduced left ventricular ejection fraction less than 40%, then the blood level of the biomarker of myocardial fibrosis sST2 is assessed, the value of the sST2 biomarker is compared with the reference threshold value, and when the sST2 level is less than 45 ng / ml, a low risk of developing cardiovascular complications due to small cardiac output syndrome is established in the early postoperative period, and if the sST2 level is more than 45 ng / ml, it is concluded that there is a high risk of developing cardiovascular complications in the early postoperative period due to the syndrome of small cardiac output after open heart surgery.