RU2804705C1 - Method for predicting risks of progression of chronic heart failure with preserved ejection fraction in patients with non-obstructive atherosclerosis of coronary arteries during 12 months of observation - Google Patents

Abstract

FIELD: medicine; cardiology; angiology; cardiac surgery; rehabilitation.

SUBSTANCE: invention can be used to predict the risk of progression of chronic heart failure with preserved ejection fraction (CHFPEF) in patients with non-obstructive atherosclerosis of the coronary arteries during 12 months of observation. In patients immediately after the diagnosis of CHFPEF, the serum level of the N-terminal fragment of brain natriuretic hormone (B-type) (NT-proBNP) is determined using an enzyme-linked immunosorbent assay and the value of myocardial blood flow reserve (MFR) using dynamic single-photon emission tomography of the myocardium. If the NT-proBNP level is 760.5 pg/mL or more and MFR is 1.62 or less, a high risk of progression of CHFPEF is predicted.

EFFECT: method provides the ability to improve the quality of predicting the risk of progression of CHFPEF in patients with non-obstructive atherosclerosis of the coronary arteries during 12 months of observation by determining the content of NT-proBNP in the blood serum and the value of myocardial blood flow reserve MFR.

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Description

The invention relates to medicine and can be used in cardiology, therapy, cardiac surgery, rehabilitation to improve the quality of predicting the progression of chronic heart failure with preserved ejection fraction (CHFpEF) in patients with non-obstructive atherosclerosis of the coronary arteries during 12 months of observation.

Studies over the past 10 years have shown that CHFpEF is becoming an increasingly prevalent form of heart failure, the prevalence of which over this period, compared with CHF with reduced EF, has increased by an average of 10-20% [1]. This is largely due to the fact that currently no class of drugs has proven the ability to reliably reduce mortality and morbidity in HFpEF [2], which, in turn, is due to the lack of a common view on the mechanisms of formation of this pathology [3].

It is known that occlusive lesions of the coronary arteries (CA) are one of the triggers for the formation and progression of HFpEF. However, recently, data have appeared indicating that patients with non-obstructive atherosclerosis of the coronary artery, despite preserved LVEF, are more susceptible to hospitalization due to decompensated CHF [4]. Recently, a new innovative theory of the development and progression of CHFpEF has been proposed, in particular in patients with non-occlusive atherosclerosis of the coronary artery, which is based on damage to the coronary microvascular bed [5]. It has been established that 53% of patients with non-obstructive lesions of the coronary artery and anginal pain show signs of stress-induced myocardial ischemia [6]. According to a meta-analysis of 56 studies involving 14,427 patients, the proportion of patients with coronary microvascular disease in the general population was 41%, and in patients with HFpEF the prevalence increased to 75-85% [7].

A recognized method for visualizing microvascular dysfunction of the coronary circulation is positron emission tomography (PET) [8]. However, at the moment, the use of PET to assess absolute parameters of myocardial perfusion has not found widespread use in clinical practice due to the complexity and high cost of the procedures. Another method for determining absolute perfusion parameters is dynamic single-photon emission tomography (SPECT) of the myocardium [9]. This technique has emerged relatively recently with the advent of a new class of gamma cameras equipped with semiconductor cadmium-zinc-telluride (CZT) detectors, which allow quantitative determination of myocardial flow reserve (MFR) and myocardial blood flow through dynamic imaging with good accuracy and correlation. At the same time, the method, along with PET, has been sufficiently tested and validated, and is also a more accessible method for visualizing microcirculatory changes in the coronary bed [10].

Molecular imaging methods are becoming a new tool for non-invasive identification of a wide range of biological processes occurring in organ tissue during the development of the disease even before the manifestation of significant anatomical features or the development of complications, in particular during atherogenesis [11]. The use of molecular biomarkers as a component of a combined imaging strategy, taking into account PET or SPECT data, can improve diagnostic yield by providing additional information related to morphology and function that is important for further clinical management of patients [12]. This determines the choice of method for developing a method for non-invasively predicting the progression of chronic heart failure with preserved ejection fraction in patients with non-obstructive atherosclerosis of the coronary arteries.

There is a known method for non-invasive early diagnosis of damage to the coronary microvascular bed in patients with non-obstructive atherosclerosis of the coronary arteries. In the blood serum of patients, after identifying non-obstructive atherosclerotic lesions of the coronary arteries, the concentration of soluble ST2 is determined using an enzyme-linked immunosorbent assay. When the level of soluble ST2 is 31.304 ng/ml or more, damage to the coronary microvascular bed is diagnosed [13]. However, using this method, in patients with non-obstructive atherosclerosis of the coronary arteries, damage to the coronary microvascular bed is directly diagnosed, but not the nature of the course of developed CHFpEF.

No adequate prototype was found in the analyzed patent and scientific medical literature.

The objective of the invention is to create a method for predicting the progression of chronic heart failure with preserved ejection fraction in patients with non-obstructive atherosclerosis of the coronary arteries over 12 months of observation. This problem is solved by determining NT-proBNP in blood serum using the enzyme immunoassay method and MFR using dynamic single-photon emission tomography of the myocardium immediately after the diagnosis of CHFpEF. With NT-proBNP values of 760.5 pg/ml or more and MFR of 1.62 or less, a high risk of progression of chronic heart failure with preserved ejection fraction in patients with non-obstructive atherosclerosis of the coronary arteries is predicted during 12 months of observation (AUC 0.935; sensitivity 90. 1%, specificity 87.5%; p<0.001).

What is new in the proposed method is that to assess the risk of progression of CHFpEF in patients with non-obstructive atherosclerosis of the coronary arteries, NT-proBNP levels are determined in the blood serum using an enzyme-linked immunosorbent method and the MFR value is assessed using dynamic single-photon emission tomography of the heart.

Currently, the most accepted hypothesis about the pathogenesis of HFpEF suggests that concomitant diseases, such as metabolic syndrome, obesity, arterial hypertension, diabetes mellitus, chronic kidney disease, etc., can initiate a systemic inflammatory response that contributes to the development of oxidative stress in endothelial cells, deteriorating their function and reducing the bioavailability of nitric oxide either due to direct effects or overexpression of endothelin-1 [4]. The endothelium plays a key role in preventing platelet aggregation and leukocyte adhesion, regulating cell proliferation, and modulating vascular tone through the synthesis and release of endothelial vasodilating components, including prostaglandins, nitric oxide, and endothelium-dependent hyperpolarizing factors. Thus, on the one hand, disturbances in both the myocyte and non-myocyte compartments of the endothelium against the background of chronic systemic inflammation cause adhesion and infiltration of monocytes and stimulation of integrated macrophages, which leads to the differentiation of myofibroblasts and, ultimately, the secretion of collagen and, as a consequence, the development of myocardial fibrosis, increased rigidity, diastolic dysfunction and, as a consequence, the development of CHFpEF [7]. This suggests that factors that tip the balance toward cardiomyocyte injury may worsen myocardial mechanics and increase the risk of progression to HFpEF even in the setting of non-obstructive coronary artery disease. The combination of one of the dynamic SPECT indicators of myocardial blood flow reserve, reflecting damage to the microvasculature, with a biomarker of volume overload - NT-proBNP - indicates a closer connection between these processes, which, in particular, confirms the pathogenesis of the development of HFpEF [5].

The advantage of the proposed invention is to increase the efficiency of predicting the progression of a socially significant disease, which makes it possible to:

- predict the progression of CHFpEF in the early stages and prescribe pathogenetic, optimally personalized therapy aimed at restoring coronary blood flow and myocardial metabolism;

- to identify a priority group of patients with non-obstructive lesions of the coronary arteries and an increased risk of progression of chronic heart failure for clinical observation and optimization of targeted preventive measures aimed at preventing extremely high premature mortality of the population;

- reduce the large financial costs of healthcare associated with expensive treatment of widespread pathology of the working population of the state.

Significant features have been revealed in the claimed set of new properties that do not clearly follow from the state of the art in this field and are not obvious to a specialist. An identical set of signs was not found in the analyzed literature. The proposed invention can be used in healthcare.

Based on the above, the invention should be considered to comply with the conditions of patentability “Novelty”, “Inventive step”, “Industrial applicability”.

The invention will be clear from the following description and the accompanying figures.

In fig. Figure 1 presents the results of ROC analysis. The ROC curve of the sensitivity and specificity characteristics of NT-proBNP and MFR in assessing the risk of progression in patients with non-obstructive atherosclerosis of the coronary arteries is shown: the y-axis is the frequency (%) of true positive results (sensitivity), the x-axis is the frequency (%) of false positive results (100 minus specificity). According to the analysis, it follows that the “cut-off point” characterizing the risk of progression of CHFpEF is the NT-proBNP level equal to or more than 760.5 pg/ml and the MFR level equal to or less than 1.62 (AUC 0.935; sensitivity 90.1% , specificity 87.5%; p<0.001) (Fig. 1).

The method is carried out as follows:

Immediately after the diagnosis of CHFpEF is made in patients with non-obstructive atherosclerosis of the coronary arteries, the content of NT-proBNP is determined in the blood serum and dynamic SPECT is performed.

Determination of the level of NT-proBNP in blood serum is carried out by enzyme-linked immunosorbent assay (ELISA), using a commercial kit from Biomedica, Austria.

Material used: The Biomedica test uses human serum samples obtained from peripheral venous blood collected from the cubital vein in the morning, on an empty stomach, into vacuum blood collection systems.

Collection and storage of samples: centrifugation and separation of serum or plasma from blood cells is carried out within 4 hours from the moment of blood collection. To obtain serum or plasma, peripheral blood is centrifuged at 3000 rpm for 10 minutes. Aliquots of samples are stored at - 24°C.

Preparation for dynamic SPECT includes the abolition of beta-blockers, nitrates, calcium channel antagonists 24 hours before, and methylxanthine derivatives (tea, coffee, chocolate) 24 hours before the pharmacological test.

The study is performed in the morning, on an empty stomach, according to a two-day rest-load protocol. On the first day, a study is carried out in a state of functional rest. The patient is placed supine under the gamma camera detector, with the left arm behind the head. A peripheral intravenous catheter is placed in the patient's right arm. To accurately position the left ventricle in the center of the field of view of the detectors, non-contrast computed tomography of the heart region is performed (radiation dose 0.25 mSv). Then the recording of the scintigraphic study begins. After 5 s, 99mTc-MIBI (methoxy-isobutyl-isotnitrile) in a dose of 260-444 MBq in a volume of 5 ml at a rate of 1 ml/s is administered directly through the catheter, after which a solution of 0.9% NaCl is injected in a volume of 30 ml with speed 2 ml/s. Registration of scintigraphic images is carried out for 10 minutes in tomographic ECG-synchronized mode (16 frames per cardiac cycle). The total duration of the study (including positioning the patient) is 20 minutes. After 60 minutes, standard ECG-synchronized myocardial perfusion scintigraphy (PSM) is performed.

On the second day, a study is carried out under conditions of a stress test (pharmacological stress test). The patient is placed supine under the gamma camera detector, with the left arm behind the head. One peripheral intravenous catheter is installed in the patient's right and left arms. To accurately position the left ventricle in the center of the field of view of the detectors, non-contrast computed tomography of the heart region is performed (radiation dose 0.25 mSv). To perform the study, the stress agent adenosine triphosphate (ATP) is used, which is administered intravenously into the left arm using an infusion pump at a dosage of 160 mcg/kg/min for four minutes. In the second minute, recording of scintigraphic images begins and a bolus of 99mTc-MIBI is injected into the catheter in the right arm at a dose of 260-444 MBq in a volume of 5 ml at a rate of 1 ml/s, after which a 0.9% NaCl solution is injected in a volume of 30 ml at a rate 2 ml/s. The study is carried out under the control of heart rate, blood pressure, and electrocardiogram. Registration of scintigraphic images is carried out for 10 minutes in tomographic ECG-synchronized mode (16 frames per cardiac cycle). The total duration of the study (including positioning the patient) is 20 minutes. After 60 minutes, a standard ECG-synchronized PSM is performed.

All studies are performed on a Discovery NM/CT 570c hybrid computed tomograph (GE Healthcare, Milwaukee, WI, USA), equipped with a gamma camera with highly sensitive semiconductor cadmium-zinc-telluride detectors (Cadmium-Zinc-Telluride, CZT). Scintigraphic images are recorded using a low-energy multi-pinhole collimator in 19 projections into a 32x32 pixel matrix (2.46x2.46 mm). The center of the energy window is set to the photopeak 99mTc 140 keV; The width of the energy window is symmetrical and amounts to 20%.

The resulting scintigraphic images are processed on a specialized Xeleris II workstation (GE Healthcare, Haifa, Israel). Myocardial perfusion, blood flow and reserve are assessed using specialized software Corridor 4DM SPECT and 4DM Reserve v.2015 (INVIA, Ann Arbor, MI, USA).

According to dynamic single-photon emission computed tomography of the myocardium, the values of coronary blood flow are determined against the background of a pharmacological stress test and under resting conditions, and then the global reserve of coronary blood flow is determined (as the ratio of blood flow at rest to blood flow under load.

To determine quantitative indicators of myocardial perfusion - calculation of coronary blood flow reserve (MFR) based on native data of the passage of a bolus of radiopharmaceutical drug through the cavities and tissue of the left ventricular myocardium, activity-time curves are constructed. Based on the obtained curves and the Net Retention blood flow model (1), the accumulation index of the radionuclide tracer by myocardial tissue -R is calculated [14]:

Subsequently, using the Renkin-Crone equation, the value of myocardial blood flow (MBF) is calculated [Klein. 2010]:

R=MBF (1-0.874*e-0.443/MBF)

Calculation of coronary blood flow reserve is performed using the formula:

MFR = stress-MBF/rest - MBF,

where stress-MBF is the value of myocardial blood flow against the background of a pharmacological stress test, (ml/min/g); rest-MBF is the value of myocardial blood flow under resting conditions, (ml/min/g).

The study included 59 patients with non-obstructive coronary artery disease and HFpEF (LVEF 62 [58; 66]%). The study was conducted in accordance with the provisions of the Declaration of Helsinki and approved by the local Ethics Committee of the Research Institute of Cardiology, Tomsk National Research Medical Center of the Russian Academy of Sciences (protocol No. 177 of October 30, 2018). Informed written consent was obtained from all patients before inclusion in the study. A specially designed clinical card was filled out for each patient.

All patients included in the study underwent a 6-minute walk test (SWT) and spirometry to exclude pathology of the pulmonary system as a manifestation of shortness of breath. Echocardiography (EchoCG) with assessment of parameters of diastolic dysfunction was performed using an EPIQ device (Philips Ultrasound, Inc., USA).

All patients underwent coronary computed tomographic angiography to verify atherosclerosis and assess the degree of stenosis of the coronary arteries. For contrast-enhanced scanning, 70–90 mL of nonionic contrast agent (iopamidol 370 mg, Bracco Diagnostics, Italy) was administered intravenously through an 18-gauge cubital catheter at a flow rate of 5–5.5 mL/s.

Statistical processing of the results was carried out using the statistical software package STATISTICA (StatSoft, Inc.) and MedCalc 11.5.0.0. Quantitative variables were defined as the median (Me), as well as the 25th and 75th quartiles (25Q and 75Q). To test statistical hypotheses when comparing 2 independent groups, the Mann-Whitney test was used. When analyzing qualitative characteristics, contingency tables were analyzed using Pearson's X2 criterion. If there were cells with an expected frequency less than 5, then a two-tailed Fisher's exact test or Yates correction (for 2x2 tables) was used. ROC analysis with area under the curve (AUC) calculation was used to determine NT-proBNP and MFR levels as prognostic markers for progression of HFpEF. The critical significance level p-value for all statistical analysis procedures used was taken equal to 0.05.

After 12 months of observation, the patients were retrospectively divided into 2 groups: group 1 (n=11) included patients with an unfavorable course of HFpEF, group 2 (n=47) - with a favorable course. According to the main clinical and demographic characteristics, the groups were comparable, except for the values of natriuretic peptide (p <0.001). In group 1, the level of NT-proBNP was 3.8 times higher than in group 2 (284.5 [183.42; 716.73] and 1071.4 [272.4; 2168.1] pg/ml, respectively ), and MFR values were lower in group 1 by 45.4% (p<0.001) than in group 2 (1.19 [0.86; 1.55] vs. 2.18 [1.7; 2. 55], respectively) (Table 1).

Table 1 - Clinical and instrumental characteristics of the examined patients depending on the nature of the course of HFpEF Parameter Group 1
Unfavorable course
n=11 Group 2
Favorable course
n=48 p-value Age, years 62 (54.0; 67.0) 60.0 (53.0; 68.0) 0.124 Floor (m), abs. (%) 7 (63.6) 29 (60.4) 0.912 NT-proBNP, ng/ml 1701.4 (272.4; 2168.1) 284.5 (183.4; 716.7) <0.001 LVEF, % 59.5 (56; 62.5) 61 (59; 64) 0.456 LV ESD, ml 43 (38; 47) 41.5 (36.5; 45.5) 0.544 LV EDR, ml 56.0 (49.5; 59.0) 54.5 (47.5; 57.5) 0.398 MFR 1.19 (0.86; 1.55) 2.18 (1.7; 2.55) <0.001 Notes. LVEF - left ventricular ejection fraction; LV EDR - end diastolic size of the left ventricle; LV ESD - end systolic size of the left ventricle; CFR - coronary flow reserve.

Data analysis revealed MFR levels ≤1.62 (AUC=0.827; sensitivity 84.2%, specificity 75.9%; p<0.001) and NT-proBNP ≥760.5 pg/ml (AUC=0.708; sensitivity 63 .6%, specificity 82.1%; p=0.040) can be considered as markers of adverse outcomes. At the same time, the combined determination of NT-proBNP with MFR was more significant (AUC 0.935; sensitivity 90.1%, specificity 87.5%; p<0.001) in risk stratification compared to the monomarker model.

EXAMPLE 1: Patient L. (male, 53 years old)

Mixed complaints of shortness of breath with moderate exertion - climbing to the 2nd floor, walking in a straight line up to 200-300 meters. Takes cardiomagnyl 75 mg/day, atorvastatin 40 mg/day, perindopril 5 mg/day. BMI 28.7 kg/ ^m2 . Experience in arterial hypertension - 2 years, ischemic heart disease - 6 months.

On objective examination: pulse 71 beats/min, blood pressure 120/70 mmHg. Art., respiratory rate 14 per minute, no edema.

ECG: sinus rhythm, no changes detected.

TSH 410 meters.

MSCT-CAG: balanced type, narrowing of the left artery trunk - 10%; proximal segment of the LAD - 20%; middle segment of PNA - 20%; middle OA segment - 20%; proximal segment of the RCA - 30%.

EchoCG: EF - 64%; KDO - 117 ml; KSO - 39 ml; The cavities are not enlarged, there is no hypertrophy of the chambers. General contractility is normal, no violation of local contractility was detected. Type 1 diastolic dysfunction. Valves unchanged.

NT-proBNP - 2168.1 pg/ml.

According to dynamic single-photon emission tomography of the myocardium in patient L., the myocardial blood flow reserve was equal to 1.31.

Diagnosis: IHD: angina pectoris FC I. Background: stage 3 hypertension, controlled course. Risk 4. CHF I, FC II (NYHA).

After 10 months, the patient registered progression of CHFpEF in the form of an increase from functional class II to III (according to NYHA). Torsemide 5 mg was added to the treatment. Thus, in patient L. with newly diagnosed CHFpEF with non-obstructive atherosclerosis of the coronary arteries, with an MFR level of less than 1.62 and NT-proBNP more than 760.5 pg/ml, progression of CHFpEF was recorded during 12 months of observation.

Example 2: patient V. (51 years old, male)

Mixed complaints of shortness of breath with moderate exertion - climbing to the 3rd-4th floor, walking in a straight line up to 400 meters, quickly climbing uphill. She takes cardiomagnyl 75 mg/day, rosuvastatin 10 mg/day, ramipril 2.5 mg/day. BMI 30.1 kg/ ^m2 . Experience in arterial hypertension - 3 years, ischemic heart disease - 3 months.

On objective examination: pulse 68 beats/min, blood pressure 120/80 mmHg. Art., respiratory rate 14 per minute, no edema.

ECG: sinus rhythm, no changes detected.

TSH 480 meters.

MSCT-CAG: balanced type, stenosis of the proximal segment of the LAD - 30%; middle segment of PNA - 30%; proximal segment of the RCA - 40%.

EchoCG: EF - 64%; KDO - 119 ml; KSO - 40 ml; The cavities are not enlarged, there is no hypertrophy of the chambers. General contractility is normal, no violation of local contractility was detected. Type 1 diastolic dysfunction. Valves unchanged.

NT-proBNP - 165.8 pg/ml.

According to dynamic single-photon emission tomography of the myocardium, the myocardial blood flow reserve in patient V. was equal to 2.83.

Diagnosis: IHD: angina pectoris FC I. Background: stage 3 hypertension, controlled course. Risk 4. CHF I, FC I (NYHA).

Over the course of 12 months, the patient did not experience any progression of HFpEF. Thus, in patient V. with newly diagnosed HFpEF with non-obstructive atherosclerosis of the coronary arteries, with an MFR level of more than 1.62 and NT-proBNP less than 760.5 pg/ml, progression of HFpEF was not recorded during 12 months of observation.

The proposed method was tested on 59 patients and makes it possible to predict the risk of progression of chronic heart failure with preserved ejection fraction in patients with non-obstructive atherosclerosis of the coronary arteries during 12 months of observation immediately after the diagnosis of CHFpEF. This makes it possible to identify a priority group of patients with non-obstructive atherosclerosis of the coronary arteries for follow-up with the organization of effective targeted measures aimed at preventing the progression of CHFpEF and preventing high premature mortality in these patients.

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Claims (1)

A method for predicting the risk of progression of chronic heart failure with preserved ejection fraction in patients with non-obstructive atherosclerosis of the coronary arteries during 12 months of observation, characterized by the fact that in patients immediately after the diagnosis of chronic heart failure with preserved ejection fraction, the content of the N-terminal fragment in the blood serum is determined brain natriuretic hormone (B-type) (NT-proBNP) using enzyme immunoassay and the value of myocardial blood flow reserve (MFR) using dynamic single-photon emission tomography of the myocardium and when the level of NT-proBNP is 760.5 pg/ml or more and MFR 1, A score of 62 or less predicts a high risk of progression to chronic heart failure with preserved ejection fraction.