RU2406436C1 - Method for prediction of endothelial function condition in antihypertensive therapy - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to clinical pharmacology. It involves the calculation of a vegetative balance coefficient (VBC) by formula

where SDNN is a standard deviation of a full RR indices array, Tp is total RR interval spectrum power, Am is mode amplitude; SDNN_ref, Tp_ref, Am_ref indices are recorded before the therapy starts, SDNN_ther, Tp_ther, Am_ther - with underlying antihypertensive preparations prescribed. Also an

adrenoreactivity coefficient (AC) is calculated by formula

where β-ARM_ref is sensitivity of β-adrenoreceptor of erythrocytic membranes before the administration of the prescribed preparation starts, β-ARM_ther - with underlying pharmacotherapy. If 4-week antihypertensive pharmacotherapy gives the VBC value less than 1.0 standard units and the AC value more than or equal to 0.61, the endothelial function condition is predicted as favourable. If the VBC value is more than or equal to 1.01 standard units, while the AC value is less than 0.6 standard units, impaired endothelium-dependent vasodilatation is predicted.

EFFECT: method provides the quantitative estimation of the endothelial function condition to correct the prescribed pharmacotherapy.

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Description

The invention relates to medicine, namely clinical pharmacology, and can be used to identify an individual reaction to ongoing antihypertensive therapy and determine an individual set of drugs for its correction.

There is a method of clinical and pathogenetic profiling of patients with arterial hypertension (AH), used in the selection of antihypertensive drugs (A.V. Barsukov, S.B.Shustov Arterial hypertension. Clinical profiling and choice of therapy. - St. Petersburg, 2004. - 255 S.), in which it is proposed to take into account the vegetative status, type of hemodynamics, blood pressure response to physical and psychoemotional stress. The authors suggest that patients isolate hyperadrenergic, hypervolemic, calcium-dependent forms of hypertension, determine the level of renin and the presence of genetic defects.

The disadvantage of this method is the lack of monitoring the state of the autonomic balance with the determination of endothelium dependent vasodilation on the background of pharmacotherapy, followed by the correction of drug administration depending on the individual reaction of the patient.

A known method of determining individual sensitivity to antihypertensive drugs, taking into account the damage to target organs, risk factors, the presence of concomitant diseases (Olbinskaya LI, Morozova TE, Pharmacotherapy for hypertension. - M., publishing house "Russian doctor", 2002 ) The disadvantage of this method is the determination of indicators of the cardiovascular system without evaluating the endothelium of dependent vasodilation, which reduces the accuracy of diagnosis and does not allow us to offer individual treatment.

Currently, several methods have been proposed for determining endothelial dysfunction during antihypertensive therapy (Kobalava Zh.D., Kotovskaya Yu.V., Moiseev BC Arterial hypertension. Keys to diagnosis and treatment. - M .: GEOTAR-Media, 2009. - С .106-108). The disadvantage of this method is the determination of indicators of the functional state of the endothelium without predicting their changes against the background of the therapy, which does not allow us to offer an individual set of drugs.

The aim of the invention is the creation of quantitative diagnostic criteria for predicting the state of endothelial function in patients with arterial hypertension while taking antihypertensive drugs with the definition of individual hypotensive therapy.

This goal is achieved using two new diagnostic criteria - the coefficient of autonomic balance (CVB) and the coefficient of adrenore activity (CA). To assess the endothelium of dependent vasodilation, an increase in the pulse wave amplitude (PAPV) determined by the oscillographic method on the brachial artery is taken into account before and after a 3-minute occlusal test (the norm is more than 1.5 conventional units).

The vegetative balance coefficient is determined by the results of a study of heart rate variability indicators according to the formula (1):

where SDNN is the standard deviation of the full array of RR indicators,

Tr is the total power of the spectrum of cardio intervals,

Am is the amplitude of the mode.

Indicators SDNN _icx, Tr _{ref, ref} Am registered to the start of therapy,

SDNN _ter , Tr _ter , Am _ter - while taking antihypertensive drugs.

The adrenoreactivity coefficient (KA) is determined by the formula (2):

,

,

where β-AWP _ref is the sensitivity of β-adrenergic receptors of erythrocyte membranes before taking drugs,

β-APM _ter - sensitivity of β-adrenergic receptors of erythrocyte membranes against the background of ongoing pharmacotherapy.

We examined 42 patients suffering from hypertension of the I-II stage, who received antihypertensive therapy (ACE inhibitors and beta-blockers in monotherapy or as part of combination therapy). Before treatment, all patients were examined using standard methods (Russian guidelines for the diagnosis and treatment of hypertension, 3rd revision, 2008), including blood pressure, ECG, echocardiography, a general analysis of blood and urine, and plasma glucose, serum cholesterol, creatinine, uric acid.

In addition, additional diagnostic coefficients (CVB, CA) were calculated in patients taking into account the data of heart rate variability (Varicard, Russia) and sensitivity indicators of erythrocyte membrane β-adrenergic receptors (β-AWP) (Struk R.I., Dlusskaya I.G. Method for assessing the adrenoreactivity of an organism by the value of beta-adrenoreception of cell membranes: guidelines. - M.: MGMSU, 2000. - 11 pp.) And determined endothelium-dependent vasodilation by an oscillographic method after a 3-minute occlusion test (Angioscan, Russia).

Monitoring of blood pressure, endothelium-dependent vasodilation and autonomic regulation with the calculation of diagnostic coefficients was performed before therapy, after 4 and 8 weeks of taking antihypertensive drugs. Efficiency criterion was the achievement of the target blood pressure level of less than 140/90 mm Hg, which was consistent with the recommendations of GFCF (2008).

According to the results of observation after 4 weeks of pharmacotherapy, two groups of patients were identified. The first group consisted of 35 patients (83%) who had a decrease in blood pressure and a decrease in the activity of the sympatho-adrenal system (CVB less than 1.0 conv. Units) without a significant increase in the sensitivity of β-adrenergic receptors (CA is greater than or equal to 0.61 conv. units). At the same time, in this group of patients, the indices of endothelium-dependent vasodilation, according to the occlusal test, tended to improve, which indicated a positive dynamics in the state of the vascular endothelium. Further, with the continuation of the antihypertensive therapy, which was carried out in the previous regimen of taking the drugs, after 8 weeks of observation in patients of the selected group, the achievement of the target blood pressure level of less than 140/90 mm Hg was noted

In patients of the second group, in the amount of 7 people, after 4 weeks of antihypertensive therapy against the background of a decrease in blood pressure, an increase in the activity of the sympathetic link of autonomic regulation (CAB is greater than or equal to 1.01 conventional units) and a significant increase in the sensitivity of β-adrenergic receptors (CA less than 0 , 6 conventional units). At the same time, endothelial dependent vasodilation indices tended to worsen compared with the results before therapy or remained unchanged. Continuation of antihypertensive pharmacotherapy in patients of the second group without changes in the regimen of drugs showed that after 8 weeks of treatment, these patients exacerbated the autonomic imbalance with a marked increase in the sensitivity of the receptor apparatus and a deterioration in the endothelium dependent vasodilation. This was accompanied by a decrease in the effectiveness of antihypertensive therapy with an increase in predominantly diastolic blood pressure, while the target blood pressure was less than 140/90 mm Hg. in 6 patients were not achieved.

Thus, the new diagnostic criteria make it possible after 4 weeks of taking antihypertensive drugs to identify an individual reaction to the treatment with a prognosis of a decrease in the effectiveness of therapy in 17% of patients, which is not possible using standard examination methods.

The conducted studies allowed us to formulate the following rules:

If after 4 weeks of pharmacotherapy, CA is greater than or equal to 0.61, which is associated with a moderate change in β-adrenoreceptor adrenoreactivity, and the CVB value is less than 1.0 conventional units, which indicates a decrease in the activity of the sympathetic department of autonomic regulation, a prognosis for the state of endothelial function favorable and ongoing pharmacotherapy can be continued.

If after 4 weeks of antihypertensive therapy, CVB is greater than or equal to 1.01 conventional units, CA is less than 0.6 conventional units, which is associated with an increase in the activity of the sympathetic department of autonomic regulation in combination with a significant increase in receptor adrenoreactivity, the prognosis of endothelial function is poor and ongoing pharmacotherapy requires correction.

Determination of diagnostic criteria in patients with hypertension (CVB and CA) in the presence of antihypertensive therapy allows timely correction of the prescription of drugs, helping to increase the effectiveness of antihypertensive therapy.

The method is illustrated by the following examples:

Example 1

Patient B., 33 years old, diagnosis: hypertension of the 1st century, the risk of MTR ₂ .

Before pharmacotherapy (02/27/2009), according to daily monitoring, the average daily blood pressure indicators are 145/100 mm Hg, the results of determining heart rate variability indicators: SDNN and _{xx are} 28 ms, _TPx is 0.78 mc2 × 1000, Am _ref is 68.7%, β-AWP is equal to 46 conventional units, with an occlusal test, SAW is equal to 1.48 conventional units (the norm is more than 1.5 conventional units).

To correct arterial hypertension, the patient was assigned a selective β ₁ -blocker nebivolol (nebilet) at a dose of 2.5 mg / day.

During the follow-up examination (04/01/2009) after 4 weeks of pharmacotherapy, the average daily blood pressure indices are 130/85 mm Hg, heart rate variability indicators: SDNN is 32 ms, TP is 1.05 mc2 × 1000, Am is 57.6%, the value of β-AWP is 30 srvc, with an occlusal test of SAWP is 1.52 srvc

Calculation of diagnostic criteria:

The calculated indicator of CVB after 4 weeks of therapy was 0.81 conventional units, which indicates a decrease in the activity of the sympathetic link of autonomic regulation. In this case, the CA value is 0.65 conv.ed., indicates a moderate change in the adrenoreactivity of the receptors. The data of the occlusal test with an increase in PAPV from 1.48 conventional units up to 1.52 conventional units reflect positive changes in endothelium-dependent vasodilation compared with indicators before treatment.

Patient B. treatment with nebivolol was continued unchanged. In the control study (04/22/09) after 8 weeks of taking the drug, the average daily blood pressure was 130/85 mm Hg, heart rate variability: SDNN was 39 ms, TP was 1.54 mc2 × 1000, Am was 43.1 %, the value of β-AWP is equal to 17.3 conventional units, according to the occlusal test, SAWP is equal to 1.5 conventional units.

Calculation of diagnostic criteria:

Reduction of CVB after 8 weeks of therapy with 0.81 conventional units up to 0.61 conventional units indicates a further decrease in the activity of the sympathetic nervous system, while CA is 0.37 conventional units, which indicates the preservation of high sensitivity of the receptors. The PAPV index is 1.5 srvc, remaining without significant changes compared with the results of the occlusal test of 04/01/2009. Due to positive changes in sympathetic activity and an improvement in the endothelium of dependent vasodilation, the patient is recommended to continue taking the drug nebivolol at the previous dose.

Example 2

Patient P., 41 years old, diagnosis: hypertension II Art., Risk of MTR ₂ .

According to the daily monitoring, before the start of pharmacotherapy (May 13, 2009), the average daily blood pressure was 145/90 mm Hg, the results of determining heart rate variability were SDNN and _xx equal to 38 ms, TP _{ex was} 1.42 mc 2 × 1000, Am and _{cx are} equal to 40.2, the value of β-AWP is equal to 58.8 conventional units, the results of the occlusal test - SAW is equal to 1.83 conventional units

To correct arterial hypertension, a combination therapy was prescribed consisting of a selective β ₁ -blocker of nebivolol (nebilet) at a dose of 2.5 mg / day and an angiotensin inhibitor of the converting enzyme zofenopril (zocardis) at a dose of 30 mg / day.

During the follow-up examination (June 16, 2009), after 4 weeks of pharmacotherapy, the average daily blood pressure indicators are 130/85 mm Hg, heart rate variability indicators: SDNN is 38 ms, TP is 1.49 mc 2 × 1000, Am is 47, 8%, the value of β-AWP is equal to 20.6 conventional units, PAPV is equal to 1.41 conventional units

Calculation of diagnostic criteria:

The calculated value of CVB after 4 weeks of therapy was 1.04 conventional units, which indicates the preservation of activity of the sympathoadrenal system against the background of a marked increase in receptor adrenoreactivity (CA is 0.35 conventional units). Moreover, the patient noted a decrease in endothelium-dependent vasodilation, as indicated by a decrease in SAWP from 1.83 conventional units up to 1.41 conventional units (norm SAWP more than 1.5 srvc.).

The patient continued taking the drugs for another 4 weeks, during the follow-up examination (07/20/2009) the average daily blood pressure was 130/90 mm Hg, the P-arm value was 21.8 srvc, heart rate variability indicators: SDNN is 35 ms, TP is 1.22 mc 2 × 1000. Am is 54.3%. The rate of PAPV after a 3-minute occlusal test of the brachial artery is 0.67 srvc.

Calculation of diagnostic criteria:

The increase in the design indicator of the CAB to 1.19 conventional units associated with increased activity of the sympathetic nervous system. The AC indicator is equal to 0.37 conventional units indicates the preservation of high sensitivity of adrenergic receptors, and the rate of PAPV is equal to 0.67 srvc after a 3-minute occlusal test of the brachial artery (the norm is more than 1.5 conventional units) indicates a deterioration in the endothelium of dependent vasodilation. The patient is recommended to change the scheme of ongoing pharmacotherapy to reduce the negative impact on endothelial function.

Example 3

Patient B., 27 years old, diagnosis: hypertension of the 1st century, the risk of MTR ₂ .

Prior to pharmacotherapy (04/03/2009), according to daily monitoring, the average daily blood pressure was 150/95 mm Hg, the results of determining heart rate variability indicators: SDNN and _xx equal to 57 ms, _TPx equal to 3.25 mc 2 × 1000, Am _ref is equal to 41.1%, β-AWP value is 57.2 conventional units, after a 3-minute occlusal test of the brachial artery PAPV is equal to 1.8 conventional units.

To correct arterial hypertension, a combination therapy was prescribed - selective β ₁ -blocker nebivolol (nebilet) at a dose of 2.5 mg / day and an inhibitor of angiotensin converting enzyme zofenopril (zokardis) at a dose of 30 mg / day.

After 4 weeks of pharmacotherapy (05/03/2009), the average daily blood pressure was 130/80 mm Hg, the value of β-AWP was 19.5 conv.un, heart rate variability indices: SDNN was 34 ms, TP was 1.13 mc 2 × 1000, Am is 44.9%, with an occlusive test, PAPV is 1.4 srvc.

Calculation of diagnostic criteria:

After 4 weeks of therapy, the calculated indicator of CVB was 1.87 conventional units, which indicates the activation of the sympathetic regulation link against the background of a pronounced increase in adrenoreactivity (CA equals 0.34 conventional units). At the same time, a decrease in the PAPV index from 1.8 conventional units was established. to 1.4 srvc, which indicates a decrease in endothelium-dependent vasodilation.

Pharmacotherapy was not corrected in the patient; after 8 weeks of taking nebivolol and zocardis during the follow-up study (07/02/2009), the blood pressure index was 125/90 mmHg, β-AWP was 8.4 conv.un, heart rate variability indicators: SDNN is 30 ms, TP is 1.2 mc 2 × 1000, Am is 46.2%, PAPV after a 3-minute occlusal test is 0.7 conv.

Calculation of diagnostic criteria:

The calculated indicator of CVB after 8 weeks of therapy was 1.9 conventional units, which indicates the preservation of activity of the sympathetic nervous system. In this case, the spacecraft is 0.15 srvc. and indicates a further increase in the sensitivity of adrenergic receptors. The rate of PAPV is reduced to 0.7 conventional units, indicating a further deterioration of endothelium-dependent vasodilation. In this clinical case, a deterioration in endothelial function is noted, which is associated with a vegetative imbalance and a sharp increase in receptor adrenoreactivity. It was recommended that the patient change the treatment regimen to reduce the negative impact on endothelial function.

Claims (1)

A method for predicting the state of endothelial function in patients with arterial hypertension while taking antihypertensive drugs to determine individual antihypertensive therapy, characterized in that the coefficient of vegetative
balance sheet (CVB) according to the formula

where SDNN is the standard deviation of the full array of RR indicators; Tp is the total power of the spectrum of cardio intervals; Am is the amplitude of the mode;
indicators SDNN _ref , Tp _ref , Am _ref recorded before the start of therapy, SDNN _ter , Tp _ter , Am _ter - while taking antihypertensive drugs; and adrenoreactivity coefficient (CA) according to the formula

,
where β-AWP _ref is the sensitivity of β-adrenergic receptors of erythrocyte membranes before taking the drugs; β-APM _ter - sensitivity of β-adrenergic receptors of erythrocyte membranes against the background of ongoing pharmacotherapy; if after 4 weeks of antihypertensive pharmacotherapy, the value of the CVB is less than 1.0 srvc. and CA is greater than or equal to 0.61, the prognosis of endothelial function is favorable, correction of the prescribed course is not required; if CVB is greater than or equal to 1.01 conventional units, CA is less than 0.6 conventional units, endothelium-dependent vasodilation worsens and the prescribed course of pharmacotherapy is corrected.