Angina pectoris clinical recommendations. IV functional class

For quotation: Lupanov V.P. New European guidelines 2013 for the treatment of stable coronary heart disease // Breast Cancer. 2014. No. 2. P. 98

In September 2013, updated guidelines from the European Society of Cardiology (ESC) for the treatment of stable ischemic (coronary) heart disease (CHD) were published. The purpose of these recommendations is to assist clinicians in selecting the optimal treatment for an individual patient with stable coronary artery disease in daily practice. The recommendations discuss indications for use, interactions and side effects of main medications, and assess possible complications in the treatment of patients with stable coronary artery disease.

Treatment Goals
There are two main goals of pharmacological treatment in patients with stable CAD: symptomatic relief and prevention of cardiovascular complications.
1. Relief of angina symptoms. Fast-acting nitroglycerin preparations can provide immediate relief of angina symptoms immediately after the attack begins or when symptoms may appear (angina immediate treatment or prevention). Anti-ischemic drugs, as well as lifestyle changes, regular exercise, patient education, revascularization - all of these methods play a role in minimizing or eliminating symptoms over the long term (long-term prevention).
2. Prevent the occurrence of cardiovascular events. Efforts to prevent myocardial infarction (MI) and death from CAD are primarily aimed at reducing the incidence of acute thrombus formation and the occurrence of ventricular dysfunction. These goals are achieved through pharmacological interventions or lifestyle changes and include: 1) reducing the progression of atherosclerotic plaque; 2) stabilization of the plaque by reducing inflammation; 3) prevention of thrombosis, which contributes to plaque rupture or erosion. In patients with severe coronary artery disease that supplies a large area of ​​myocardium and is at high risk for complications, a combination of pharmacologic and revascularization strategies offers additional opportunities to improve prognosis by increasing myocardial perfusion or providing alternative perfusion pathways.
In the prevention of angina attacks, pharmacological drugs that reduce the load on the heart and myocardial oxygen demand and improve myocardial perfusion usually take first place with a combined drug and revascularization strategy. Three classes of drugs are widely used: organic nitrates, β-blockers (BABs) and calcium channel blockers (CCBs).
The pathomorphological substrate of angina pectoris is almost always atherosclerotic narrowing of the coronary arteries (CA). Angina appears during physical activity (PE) or stressful situations in the presence of narrowing of the lumen of the coronary artery, usually by no less than 50-70%. The severity of angina depends on the degree of stenosis, its location, extent, number of stenoses, number of affected coronary arteries and individual collateral blood flow. The degree of stenosis, especially eccentric, can vary depending on changes in smooth muscle tone in the area of ​​the atherosclerotic plaque (AP), which manifests itself in changes in the tolerance of exercise. Often angina pectoris is mixed in pathogenesis. Along with organic atherosclerotic lesion (fixed coronary obstruction), a transient decrease in coronary blood flow (dynamic coronary stenosis), usually associated with changes in vascular tone, spasm, and endothelial dysfunction, plays a role in its occurrence.
In recent years, along with the oldest classes of drugs, such as nitrates (and their derivatives), beta blockers, CCBs, other drugs with different mechanisms of action (ivabradine, trimetazidine, partly nicorandil), as well as the new drug ranolazine, can be added to the treatment of IHD. indirectly preventing intracellular calcium overload, which is involved in reducing myocardial ischemia and is a useful addition to the main treatment (Table 1). The ESC recommendations also indicate those drugs, the use of which does not lead to an improvement in the course of stable coronary artery disease and an improvement in the prognosis of patients.

Anti-ischemic drugs
Nitrates
Nitrates promote dilation of arterioles and venous vasodilation, which leads to the relief of exertional angina syndrome. Nitrates exert their effect thanks to the active component - nitric oxide (NO), and a decrease in preload.
Short-acting drugs for an attack of angina pectoris. Sublingual nitroglycerin is the standard initial treatment for exertional angina. If angina occurs, the patient should stop, sit down (standing position provokes fainting, and lying down increases venous return and heart function) and take sublingual nitroglycerin (0.3-0.6 mg). The drug should be taken every 5 minutes until the pain goes away, or when a total dose of 1.2 mg has been taken within 15 minutes. Nitroglycerin spray acts faster. Nitroglycerin is recommended for prophylactic use when angina can be expected or predicted, for example, physical activity after meals, emotional stress, sexual activity, going outside in cold weather.
Isosorbide dinitrate (5 mg sublingually) helps to interrupt angina attacks within approximately 1 hour. Since isosorbide dinitrate is converted in the liver into the pharmacologically active metabolite isosorbide-5-mononitrate, its antianginal effect occurs more slowly (within 3-4 minutes) than at nitroglycerin. Following oral administration, the hemodynamic and antianginal effects last for several hours, providing longer-lasting protection against angina than with sublingual nitroglycerin.
Long-acting nitrates for the prevention of angina pectoris. Long-acting nitrates are ineffective if they are prescribed continuously regularly for a long time and without a free period of about 8-10 hours (development of nitrate tolerance). Progression of endothelial dysfunction is a potential complication of long-acting nitrates, and the routine use of long-acting nitrates as first-line therapy in patients with exertional angina, observed in general practice, needs to be reconsidered.
Isosorbide dinitrate (oral medication) is often prescribed to prevent angina. In a comparative placebo-controlled study, it was shown that the duration of physical activity increased significantly within 6-8 hours after a single oral dose of the drug in doses of 15-120 mg; but only for 2 hours - after taking the same dose 4 times a day, despite the higher concentration of the drug in the blood plasma. Incidental administration of isosorbide dinitrate slow-release tablets twice daily is recommended, and a 40-mg morning dose followed by a 40-mg dose 7 hours later was not superior to placebo in large multicenter studies.
Mononitrates have similar dosages and effects to isosorbide dinitrates. Nitrate tolerance can be avoided by changing the dose and timing of administration, as well as by prescribing slow-release drugs. Thus, immediate-release mononitrate preparations should be used 2 times a day or very high doses of prolonged-release mononitrates should also be prescribed 2 times a day to obtain a long-term antianginal effect. Long-term therapy with isosorbide-5-mononitrate can cause endothelial dysfunction, oxidative stress and a marked increase in the expression of vascular endothelin-1, which is an unfavorable factor (increases the incidence of coronary events) in patients who have had a myocardial infarction.
Transdermal nitroglycerin patches do not provide a 24-hour effect when used for long periods of time. Intermittent use with an interval of 12 hours allows you to get an effect for 3-5 hours. However, there is no data on the effectiveness of the second and third doses of the patch during long-term use.
Side effects of nitrates. Hypotension is the most serious and headaches (acetylsalicylic acid (ASA) can reduce these) the most common side effect of nitrates (Table 2). Many patients using long-acting nitrates quickly develop tolerance. To prevent its occurrence and maintain the effectiveness of treatment, it is possible to reduce the concentration of nitrates to a low level for 8-12 hours during the day. This can be achieved by prescribing medications only at the time of day when attacks are most likely to occur.
Drug interactions. When taking nitrates with CCBs, an increased vasodilator effect is observed. Serious hypotension can occur when taking nitrates with selective phosphodiesterase (PDE5) blockers (sildenafil, etc.), which are used for erectile dysfunction and to treat pulmonary hypertension. Sildenafil reduces blood pressure by 8.4/5.5 mmHg. Art. and more significantly when taking nitrates. Nitrates should not be used with α-blockers in patients with prostate diseases. In men with prostate problems taking tamsulosin (an α1-blocker of prostate adrenergic receptors), nitrates may be prescribed.
Molsidomin. It is a direct donor of nitric oxide (NO) and has an anti-ischemic effect similar to isosorbide dinitrate. A long-acting drug, prescribed in a dose of 16 mg 1 time/day. A dose of 8 mg molsidomine twice a day is as effective as 16 mg once a day.
Beta blockers (BAB)
BBs act directly on the heart, reducing heart rate, contractility, atrioventricular (AV) conduction, and ectopic activity. In addition, they can increase perfusion in ischemic areas, prolonging diastole and increasing vascular resistance in non-ischemic areas. In patients after MI, taking beta blockers reduces the risk of cardiovascular death and MI by 30%. Thus, beta blockers may protect patients with stable coronary artery disease from cardiovascular events, but without supporting evidence in placebo-controlled clinical trials.
However, a recent retrospective analysis of the REACH registry confirmed that in patients with any CAD risk factor, prior MI, or CAD without MI, β-blocker use was not associated with a reduction in the risk of cardiovascular events. However, the analysis lacks statistical power and randomized assessment of treatment outcome. Among other limitations of this study, most trials of beta blockers in post-myocardial infarction patients were conducted before other secondary preventive interventions, such as statins and ACE inhibitors, leaving uncertainty regarding the effectiveness of beta blockers when added to current therapeutic strategies.
It has been proven that beta blockers are effective in the fight against angina pectoris during exercise, they increase exercise power and reduce both symptomatic and asymptomatic myocardial ischemia. As for the control of angina, beta blockers and CCBs have the same effect. BABs can be combined with dihydropyridines. However, the combination of beta blockers with verapamil and diltiazem should be excluded due to the risk of bradycardia or AV block. The most widely used in Europe are beta blockers with a predominant blockade of β1 receptors, such as metoprolol, bisoprolol, atenolol or nebivolol; Carvedilol, a non-selective β-α1 blocker, is also often used. All of these beta blockers reduce cardiac events in patients with heart failure. BBs should be the first line of antianginal drugs for stable coronary artery disease in patients without contraindications. Nebivolol and bisoprolol are partially excreted by the kidneys, while carvedilol and metoprolol are metabolized in the liver, therefore, the latter have a higher level of safety in patients with kidney disease.
Numerous studies have shown that beta blockers significantly reduce the likelihood of sudden death, recurrent myocardial infarction and increase the overall life expectancy of patients who have suffered an infarction. BBs significantly improve the prognosis of patients' lives if coronary artery disease is complicated by heart failure (HF). BBs have an antianginal, hypotensive effect, reduce heart rate, have antiarrhythmic and antiadrenergic properties, inhibit sinoatrial (SA) and (AV) conduction, as well as myocardial contractility. BBs are first-line drugs when prescribing antianginal therapy in patients with stable angina in the absence of contraindications. There are some differences between beta blockers that determine the choice of a particular drug for a particular patient.
Cardioselectivity is understood as the ratio of the blocking effect on β1-adrenergic receptors located in the heart and β2-adrenergic receptors located mainly in the bronchi and peripheral vessels. Currently, it is obvious that preference should be given to selective biologically active substances. They are less likely to have side effects than non-selective beta blockers. Their effectiveness has been proven in large clinical studies. Such data were obtained using sustained-release metoprolol, bisoprolol, nebivolol, and carvedilol. Therefore, these beta blockers are recommended to be prescribed to patients who have had a myocardial infarction. Based on the severity of cardioselectivity, a distinction is made between nonselective (propranolol, pindolol) and relatively cardioselective beta blockers (atenolol, bisoprolol, metoprolol, nebivolol). Bisoprolol and nebivolol have the greatest cardioselectivity. Cardioselectivity is dose-dependent; it is significantly reduced or leveled out when using beta blockers in high doses. BBs effectively eliminate myocardial ischemia and increase exercise tolerance in patients with angina pectoris. There is no evidence that any drug is superior, but sometimes a patient responds better to a particular beta blocker. Sudden withdrawal of beta blockers can cause worsening of angina, so the dose should be reduced gradually. The effectiveness of carvedilol, metoprolol and propranolol has been proven among beta blockers for long-term secondary prevention after MI. The effect of these drugs in stable angina can only be counted on if, when prescribed, a clear blockade of β-adrenergic receptors is achieved. To do this, it is necessary to maintain your resting heart rate within the range of 55-60 beats/min. In patients with more severe angina, the heart rate can be reduced to 50 beats/min. provided that such bradycardia does not cause discomfort and AV block does not develop.
Main side effects. All beta blockers reduce heart rate and can suppress myocardial contractility. They should not be prescribed to patients with sick sinus syndrome (SSNS) and grade II-III AV block. without a functioning artificial pacemaker. BBs have the potential to cause HF or worsen its course; however, with long-term use with a slow stepwise increase in dose, a number of beta blockers have a positive effect on the prognosis in patients with chronic CHF. Beta blockers (both non-selective and relatively cardioselective) can cause bronchospasm. This action is potentially very dangerous in patients with bronchial asthma, severe chronic obstructive pulmonary disease (COPD), therefore, beta blockers should not be prescribed to such patients. Only in cases where the benefit of beta blockers is undoubted, there is no alternative treatment and there is no broncho-obstructive syndrome, one of the cardioselective beta blockers can be used (with extreme caution, under the supervision of a physician, starting with very low doses and preferably with short-acting drugs) (Table 1) .
The use of beta blockers may be accompanied by a feeling of weakness, increased fatigue, sleep disturbances with nightmares (less typical for water-soluble beta blockers (atenolol)), coldness of the extremities (less typical for low doses of cardioselective beta blockers and drugs with intrinsic sympathomimetic activity (pindolol, acebutalol, oxprenolol)) . Combination therapy of beta blockers with CCBs (verapamil and diltiazem) should be avoided due to the risk of bradycardia or AV block. Only critical ischemia of the lower extremities is considered an absolute contraindication to the use of beta blockers. Diabetes mellitus (DM) is not a contraindication to the use of beta blockers. However, they may lead to some reduction in glucose tolerance and alter metabolic and autonomic responses to hypoglycemia. For diabetes, it is preferable to prescribe cardioselective drugs. In patients with diabetes with frequent episodes of hypoglycemia, beta blockers should not be used.

Calcium channel blockers (CCBs)
Currently, there is no data confirming the beneficial effect of CCBs on the prognosis of patients with uncomplicated stable angina, although drugs of this group that reduce heart rate may be an alternative to beta blockers (if they are poorly tolerated) in patients who have had a myocardial infarction and do not suffer from HF. Based on their chemical structure, derivatives of dihydropyridine (nifedipine, amlodipine, lacidipine, nimodipine, felodipine, etc.), benzodiazepine (diltiazem) and phenylalkylamine (verapamil) are distinguished.
CCBs that reflexively increase heart rate (dihydropyridine derivatives) prevent the movement of calcium ions through predominantly L-type calcium channels. They affect cardiomyocytes (reduce myocardial contractility), cells of the cardiac conduction system (suppress the formation and conduction of electrical impulses), smooth muscle cells of arteries (reduce the tone of coronary and peripheral vessels). CCBs differ in their points of action, so their therapeutic effects vary much more than those of beta blockers. Dihydropyridines have a greater effect on arterioles, verapamil affects mainly the myocardium, diltiazem occupies an intermediate position. From a practical point of view, there are CCBs that reflexively increase heart rate (dihydropyridine derivatives) and decrease heart rate (verapamil and diltiazem), and their action is in many ways similar to beta blockers. Among the dihydropyridines, there are short-acting (nifedipine, etc.) and long-acting drugs (amlodipine, lacidipine, and to a lesser extent felodipine). Short-acting dihydropyridines (especially nifedipine) promote reflex activation of the sympathetic part of the autonomic nervous system in response to a rapid decrease in blood pressure with the occurrence of tachycardia, which is undesirable and potentially dangerous, especially in patients with coronary artery disease. This effect is less pronounced when using sustained-release dosage forms and when administering beta blockers simultaneously.
Nifedipine relaxes vascular smooth muscle and dilates coronary and peripheral arteries. Compared to verapamil, it has a more pronounced effect on blood vessels and less on the heart, and does not have antiarrhythmic activity. The negative inotropic effect of nifedipine is counteracted by a decrease in the load on the myocardium due to a decrease in total peripheral resistance. Short-acting nifedipine preparations are not recommended for the treatment of angina pectoris and hypertension, since their use may be accompanied by a rapid and unpredictable decrease in blood pressure with reflex activation of the sympathetic nervous system and tachycardia.
Amlodipine is a long-acting dihydropyridine; has a greater effect on the smooth muscles of arterioles than on myocardial contractility and conductivity, and does not have antiarrhythmic activity. Prescribed for hypertension and angina pectoris. Contraindications: hypersensitivity (including to other dihydropyridines), severe arterial hypotension (SBP)<90 мм рт. ст.), обострение ИБС (без одновременного применения БАБ), выраженный стеноз устья аорты (табл. 2). Побочные эффекты: боль в животе, тошнота, сердцебиение, покраснение кожи, головная боль, головокружение, расстройства сна, слабость, периферические отеки; реже - нарушения со стороны ЖКТ, сухость во рту, нарушения вкуса. С осторожностью назначать при печеночной недостаточности (уменьшить дозу), хронической СН или выраженной сократительной дисфункции ЛЖ, обострении КБС, стенозе устья аорты или субаортальном стенозе; избегать резкой отмены (возможность усугубления стенокардии).
Amlodipine and felodipine are similar to nifedipine, but practically do not reduce myocardial contractility. They have a long duration of action and can be prescribed 1 r./day. Long-acting dosage forms of nifedipine, amlodipine and felodipine are used to treat hypertension and angina. They have a pronounced positive effect in forms of angina caused by spasm of the coronary arteries.
Lacidipine and lercanidipine are used only for the treatment of hypertension. The most common side effects of dihydropyridines are related to vasodilation: hot flash and headache (usually relieved after a few days), swelling of the ankles (only partially relieved by diuretics).
Verapamil is used to treat angina, hypertension and cardiac arrhythmias. It has the most pronounced negative inotropic effect, reduces heart rate, and can slow down SA and AV conduction. The drug worsens heart failure and conduction disorders; in high doses it can cause arterial hypotension, so it should not be used in combination with beta blockers. Contraindications: severe arterial hypotension and bradycardia; HF or severe impairment of LV contractile function; SSSU, SA blockade, AV blockade II-III stage. (if an artificial heart pacemaker is not installed); atrial fibrillation or flutter in WPW syndrome, ventricular tachycardia. Side effects: constipation; less often - nausea, vomiting, flushing of the face, headache, dizziness, weakness, swelling of the ankles; rarely: transient liver dysfunction, myalgia, arthralgia, paresthesia, gynecomastia and gingival hyperplasia during long-term treatment; after intravenous administration or in high doses: arterial hypotension, heart failure, bradycardia, intracardiac block, asystole. Cautions: grade 1 AV block, acute phase of myocardial infarction, obstructive hypertrophic cardiomyopathy, renal and liver failure (in severe cases, reduce the dose); Abrupt withdrawal may cause worsening of angina.
Diltiazem is effective for angina pectoris and cardiac arrhythmias; long-acting dosage forms are used to treat hypertension. Gives a less pronounced negative inotropic effect compared to verapamil; a significant decrease in myocardial contractility occurs less frequently, however, due to the risk of bradycardia, it should be used with caution in combination with beta blockers. Diltiazem, with its low side effect profile, has an advantage over verapamil in the treatment of angina pectoris.

Ivabradin
Recently, a new class of antianginal drugs has been created - inhibitors of If channels of sinus node cells, which selectively reduce sinus rhythm. Their first representative, ivabradine, showed a pronounced antianginal effect comparable to the effect of beta blockers. Evidence has emerged that the anti-ischemic effect is enhanced when ivabradine is added to atenolol, but this combination is safe. Ivabradine has been approved by the European Medicines Agency (EMA) for the treatment of chronic stable angina in patients with heart rate intolerant or inadequately controlled by beta blockers (more than 60 beats/min) in sinus rhythm.
According to the results of the BEAUTIFUL study, the administration of ivabradine to patients with stable angina, with LV dysfunction and with a heart rate >70 beats/min. reduces the increased risk of MI by 36% and the frequency of myocardial revascularization procedures by 30%. Ivabradine selectively suppresses If channels of the sinus node and dose-dependently reduces heart rate. The drug does not affect the conduction time of impulses along the intraatrial, atrioventricular and intraventricular pathways, myocardial contractility, or ventricular repolarization processes; practically does not change the total peripheral resistance and blood pressure. Prescribed for stable angina: in patients with sinus rhythm when it is impossible to use beta blockers due to contraindications or intolerance, as well as in combination with them. In chronic heart failure, ivabradine is prescribed to reduce the incidence of cardiovascular complications in patients with sinus rhythm and heart rate >70 beats/min.
Contraindications: heart rate<60 уд./мин., выраженная артериальная гипотония, нестабильная стенокардия и острый ИМ, синдром СССУ, СА-блокада, АВ-блокада III ст., искусственный водитель ритма сердца, одновременный прием мощных ингибиторов цитохрома Р4503A4 (кетоконазол, антибиотики-макролиды, ингибиторы ВИЧ-протеаз), тяжелая печеночная недостаточность, возраст до 18 лет. К побочным эффектам относятся: брадикардия, АВ-блокада, желудочковые экстрасистолы, головная боль, головокружение, фотопсия и затуманенность зрения; реже: тошнота, запор, понос, сердцебиение, суправентрикулярная экстрасистолия, одышка, мышечные спазмы, эозинофилия, повышение концентрации мочевой кислоты, креатинина. С осторожностью следует назначать ивабрадин при недавнем нарушении мозгового кровообращения, АВ-блокаде II ст., фибрилляции предсердий и других аритмиях (лечение неэффективно), артериальной гипотонии, печеночной и тяжелой почечной недостаточности, при одновременном приеме лекарственных средств, удлиняющих интервал QT, умеренных ингибиторов цитохрома Р4503A4 (грейпфрутового сока, верапамила, дилтиазема). При сочетании с амиодароном, дизопирамидом и другими лекарственными средствами (ЛС), удлиняющими интервал QT, увеличивается риск брадикардии и желудочковой аритмии; выраженное повышение концентрации наблюдается при одновременном применении кларитромицина, эритромицина, телитромицина, дилтиазема, верапамила, кетоконазола, интраконазола, грейпфрутового сока (исключить совместное применение); при стабильной стенокардии назначают перорально 5 мг 2 р./сут (у пожилых - 2,5 мг 2 р./сут), при необходимости через 3-4 нед. - увеличение дозы до 7,5 мг 2 р./сут, при плохой переносимости - уменьшение дозы до 2,5 мг 2 р/сут.

Nikorandil
Nicorandil is a nitrate derivative of nicotinamide, recommended for the prevention and long-term treatment of angina pectoris; it can be additionally prescribed to the therapy of beta blockers or CCBs, as well as in monotherapy if there are contraindications to them or intolerance. The structural features of the nicorandil molecule provide a dual mechanism of its action: activation of ATP-dependent potassium channels and nitrate-like action. Nicorandil dilates epicardial coronary arteries and stimulates ATP-sensitive potassium channels in vascular smooth muscle. In addition, nicorandil reproduces the effect of ischemic preconditioning - adaptation of the myocardium to repeated episodes of ischemia. The uniqueness of nicorandil lies in the fact that, unlike beta blockers, CCBs and nitrates, it not only has an antianginal effect, but also affects the prognosis of stable coronary artery disease. Large multicenter studies have demonstrated the ability of nicorandil to reduce adverse outcomes in patients with stable angina. Thus, in a prospective IONA study lasting 1.6 years in 5126 patients with stable angina on nicorandil therapy, a reduction in cardiovascular events was shown by 14% (relative risk 0.86; p<0,027) . Тем не менее, об облегчении симптомов не сообщалось. Длительное применение никорандила способствует стабилизации коронарных атеросклеротических бляшек у пациентов со стабильной стенокардией, нормализует функцию эндотелия и способствует уменьшению выраженности свободнорадикального окисления . Никорандил эффективен также у пациентов, перенесших чрескожное коронарное вмешательство. На практике была продемонстрирована способность никорандила снижать частоту развития аритмий, что также связано с моделированием феномена ишемического прекондиционирования. Имеются данные о положительном влиянии никорандила на мозговое кровообращение. В обзоре 20 проспективных контролируемых исследований было показано, что число побочных эффектов на фоне приема никорандила сравнимо с таковым при терапии нитратами, БАБ, БКК, однако никорандил в отличие от БКК не влияет на уровень АД и ЧСС . Никорандил не вызывает развития толерантности, не влияет на проводимость и сократимость миокарда, липидный обмен и метаболизм глюкозы. Прием никорандила обеспечивает одновременное снижение пред- и посленагрузки на левый желудочек, но приводит лишь к минимальному влиянию на гемодинамику.
The most common side effects of Nicoran-di-la are headache (3.5-9.5%) and dizziness (0.65%). Sometimes side effects include oral, intestinal and perianal ulcers. To reduce the likelihood of adverse reactions, it is advisable to initiate therapy with low doses of nicorandil, followed by titration until the desired clinical effect is achieved.

Trimetazidine
The anti-ischemic effect of trimetazidine is based on its ability to increase the synthesis of adenosine triphosphoric acid in cardiomyocytes with insufficient oxygen supply due to partial switching of myocardial metabolism from the oxidation of fatty acids to a less oxygen-consuming pathway - glucose oxidation. This increases coronary reserve, although the antianginal effect of trimetazidine is not due to a decrease in heart rate and myocardial contractility or vasodilation. Trimetazidine is able to reduce myocardial ischemia in the early stages of its development (at the level of metabolic disorders) and thereby prevent the occurrence of its later manifestations - anginal pain, cardiac arrhythmias, decreased myocardial contractility.
Trimetazidine, compared with placebo, significantly reduces the frequency of weekly angina attacks, nitrate consumption, and the time to onset of severe ST segment depression during exercise testing. Trimetazidine can be used either as an addition to standard therapy or as a replacement if it is poorly tolerated. The drug is not used in the United States, but is widely used in Europe, the Russian Federation and more than 80 countries around the world. Trimetazidine can be prescribed at any stage of the treatment of stable angina to enhance the antianginal effectiveness of beta blockers, CCBs and nitrates, as well as as an alternative if they are intolerant or contraindicated for use. The effect of trimetazidine on prognosis has not been studied in large studies. The drug is contraindicated in Parkinson's disease and movement disorders, tremors, muscle rigidity, restless legs syndrome.

Ranolazine
It is a partial inhibitor of fatty acid oxidation and has antianginal properties. It is a selective inhibitor of late sodium channels, which prevent intracellular calcium overload, a negative factor in myocardial ischemia. Ranolazine reduces contractility and stiffness of the myocardial wall, has an anti-ischemic effect and improves myocardial perfusion without changing heart rate and blood pressure. The antianginal efficacy of ranolazine has been shown in several studies in patients with coronary artery disease with stable angina. The drug has a metabolic effect, it reduces the myocardial oxygen demand. Ranolazine is indicated for use in combination with conventional antianginal therapy in those patients who remain symptomatic on conventional medications. Compared with placebo, ranolazine reduced the frequency of angina attacks and increased exercise capacity in a large study of patients with angina who had suffered acute coronary syndrome.
Prolongation of the QT interval on the ECG may occur while taking the drug (approximately 6 milliseconds at the maximum recommended dose), although this fact is not considered responsible for the phenomenon of torsades de pointes, especially in patients who experience dizziness. Ranolazine also reduces glycated hemoglobin (HbA1c) in patients with diabetes, but the mechanism and consequences of this have not yet been established. Combination therapy with ranolazine (1000 mg 2 times a day) with simvastatin increases the plasma concentration of simvastatin and its active metabolite by 2 times. Ranolazine is well tolerated; side effects: constipation, nausea, dizziness and headache are rare. The incidence of syncope when taking ranolazine is less than 1%.

Allopurinol
Allopurinol is an inhibitor of xanthine oxidase, which reduces uric acid in patients with gout and also has an antianginal effect. There is limited clinical evidence, but in a randomized crossover trial of 65 patients with stable coronary artery disease, administration of allopurinol at a dose of 600 mg/day increased the time of exercise before the appearance of ischemic ST-segment depression on the ECG and before the onset of chest pain. If renal function is impaired, such high doses of allopurinol may cause toxic side effects. When treated in optimal doses in patients with stable coronary artery disease, allopurinol reduced vascular oxidative stress.

Other drugs
Analgesics. The use of selective cyclooxygenase-2 (COX-2) inhibitors and traditional non-selective non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with an increased risk of cardiovascular events in recent clinical trials for the treatment of arthritis and cancer prevention and are therefore not recommended. In patients at increased risk of vascular disease associated with atherosclerosis who require pain relief, it is recommended that treatment be initiated with acetaminophen or ASA at the lowest effective dose, especially for short-term needs. If NSAIDs are required for adequate pain relief, these agents should be used in the lowest effective doses and for the shortest duration possible. In patients with atherosclerotic vascular disease and stable coronary artery disease, if treatment, in particular NSAIDs, is necessary for other reasons, low doses of ASA should be prescribed to ensure effective platelet inhibition.
In patients with low blood pressure, antianginal drugs should be started at very low doses, with predominant use of drugs that have no or limited effect on blood pressure, such as ivabradine (in patients with sinus rhythm), ranolazine or trimetazidine.
Patients with low heart rate. Several studies have shown that increased resting heart rate is an independent risk factor for poor outcome in patients with stable CAD. There is a linear relationship between resting heart rate and major cardiovascular events, with a persistent decrease in the latter at low heart rates. The use of beta blockers, ivabradine, and pulse-lowering CCBs should be avoided or, if necessary, prescribed with caution and at very low doses.

Treatment strategy
Table 1 summarizes the medical treatment of patients with stable coronary artery disease. This general strategy can be adjusted according to the patient's comorbidities, contraindications, personal preferences, and drug costs. Drug treatment consists of a combination of at least one drug to relieve angina plus drugs to improve prognosis (antiplatelet agents, lipid-lowering agents, ACE inhibitors), as well as the use of sublingual nitroglycerin to relieve attacks of chest pain.
Beta blockers or CCBs with the addition of short-acting nitrates are recommended as first-line treatment to control symptoms and heart rate. If symptoms are not controlled, switching to another option (CCB or beta blocker) or combining a BAC with a dihydropyridine CCB is recommended. The combination of pulse-lowering CCBs with beta blockers is not recommended. Other antianginal drugs may be used as second-line therapy when symptoms are not well controlled. In selected patients with intolerance or contraindications to beta blockers and CCBs, second-line drugs can be used as first line of therapy. Table 1 shows the generally accepted grades of recommendation and levels of evidence.
Prevention of cardiovascular events is optimally achieved by prescribing antiplatelet agents (low-dose ASA, P2Y12 platelet inhibitors (clopidogrel, prasugrel, ticagrelor) and statins. The use of ACE inhibitors or angiotensin receptor blockers may be considered in some patients.

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The most important diagnostic method for complaints of chest pain is taking anamnesis.
At the diagnostic stage, it is recommended to analyze complaints and collect anamnesis in all patients with suspected ischemic heart disease.

Comments. The most common complaint with angina pectoris, the most common form of stable coronary artery disease, is chest pain.
It is recommended to ask the patient about the existence of chest pain, its nature, frequency of occurrence and circumstances of disappearance.
Strength of recommendation level I (level of evidence certainty C).
Comments. Signs of typical (undoubted) angina pectoris:
Pain in the sternum, possibly radiating to the left arm, back or lower jaw, less often to the epigastric region, lasting 2-5 minutes. The equivalents of pain are shortness of breath, a feeling of “heaviness”, “burning”.
The pain described above occurs during physical activity or severe emotional stress.
The pain described above quickly disappears after stopping physical activity or after taking nitroglycerin.
To confirm the diagnosis of typical (undoubted) angina, the patient must have all three of the above symptoms simultaneously.
There are atypical variants of pain localization and irradiation. The main sign of angina pectoris is a clear dependence of the onset of symptoms on physical activity.
The equivalent of angina pectoris can be shortness of breath (even suffocation), a feeling of “heat” in the sternum, and attacks of arrhythmia during physical activity.
The equivalent of physical activity can be a crisis increase in blood pressure (BP) with an increase in the load on the myocardium, as well as a large meal.
The diagnosis of atypical angina is made if the patient has any two of the above three signs of typical angina.
Signs of non-anginal (non-anginal) chest pain:
The pain is localized alternately to the right and left of the sternum.
The pain is local, “point” in nature.
After the onset of pain, it lasts more than 30 minutes (up to several hours or days), and can be constant, “shooting” or “suddenly piercing.”
The pain is not associated with walking or other physical activity, but occurs when bending and turning the body, in a lying position, when the body is in an uncomfortable position for a long time, when breathing deeply at the height of inspiration.
The pain does not change after taking nitroglycerin.
The pain intensifies with palpation of the sternum and/or chest along the intercostal spaces.
A feature of the pain syndrome in the chest with vasospastic angina is that the pain attack is usually very strong and localized in a “typical” place - in the sternum. However, such attacks often occur at night and early in the morning, as well as when exposed to cold on exposed areas of the body.
A feature of the pain syndrome in the chest with microvascular angina is that anginal pain, in terms of qualitative characteristics and localization, corresponds to angina, but occurs some time after physical activity, and is poorly relieved by nitrates, may be a sign of microvascular angina.
If angina pectoris syndrome is identified during questioning, it is recommended to determine its functional class, depending on the tolerated physical activity.
Strength of recommendation level I (level of evidence certainty C).
Comments. There are 4 functional classes (FC) of angina according to the classification of the Canadian Society of Cardiology (Table 1).
Table 1. Functional classes of angina.

Functional class I	Functional class II	Functional class III	Functional class IV
"Latent" angina. Seizures occur only under extreme stress	Attacks of angina pectoris occur during normal exercise: fast walking, climbing uphill, up stairs (1-2 flights), after a large meal, severe stress	Attacks of angina sharply limit physical activity: they occur with little exertion: walking at an average pace< 500 м, при подъеме по лестнице на 1-2 пролета. Изредка приступы возникают в покое	Inability to perform any, even minimal, load due to angina pectoris. Seizures occur at rest. History often includes myocardial infarction, heart failure

When collecting anamnesis, it is recommended to clarify the fact of current or past smoking.
Strength of recommendation level I (level of evidence certainty C).
When collecting anamnesis, it is recommended to ask about cases of CVD in the patient’s closest relatives (father, mother, siblings).
Strength of recommendation level I (level of evidence certainty C).
When collecting anamnesis, it is recommended to ask about cases of death from CVD of the patient's closest relatives (father, mother, siblings).
Strength of recommendation level I (level of evidence certainty C).
During the medical history, it is recommended to ask about previous cases of seeking medical help and the results of such requests.
Strength of recommendation level I (level of evidence certainty C).
When collecting anamnesis, it is recommended to clarify whether the patient has previously recorded electrocardiograms, the results of other instrumental studies and conclusions on these studies.
Strength of recommendation level I (level of evidence certainty C).
During the history taking, it is recommended to ask the patient about known concomitant diseases.
Strength of recommendation level I (level of evidence certainty C).
During the history taking, it is recommended to ask the patient about all medications currently taken.
Strength of recommendation level I (level of evidence certainty C).
During the medical history, it is recommended to ask the patient about all medications that were previously discontinued due to intolerance or ineffectiveness. Level of strength of recommendation IIa (Level of evidence C).

2.2 Physical examination.

At the diagnostic stage, all patients are recommended to undergo a physical examination.
Strength of recommendation level I (level of evidence certainty C).
Comments. Typically, physical examination for uncomplicated stable ischemic heart disease has little specificity. Sometimes a physical examination can reveal signs of RF: excess body weight and signs of diabetes mellitus (DM) (scratching, dry and sagging skin, decreased skin sensitivity). Signs of atherosclerosis of the heart valves, aorta, main and peripheral arteries are very important: noise over the projections of the heart, abdominal aorta, carotid, renal and femoral arteries, intermittent claudication, cold feet, weakened pulsation of the arteries and atrophy of the muscles of the lower extremities. A significant risk factor for coronary artery disease detected during physical examination is arterial hypertension (AH). In addition, you should pay attention to the external symptoms of anemia. In patients with familial forms of hypercholesterolemia (HCH), examination can reveal xanthomas on the hands, elbows, buttocks, knees and tendons, as well as xanthelasmas on the eyelids. The diagnostic value of a physical examination increases when symptoms of complications of coronary heart disease are present - primarily signs of heart failure: shortness of breath, wheezing in the lungs, cardiomegaly, cardiac arrhythmia, swelling of the jugular veins, hepatomegaly, swelling of the legs. Identification of signs of HF during physical examination usually suggests post-infarction cardiosclerosis and a very high risk of complications, and therefore dictates the need for immediate complex treatment, including possible myocardial revascularization.
During the physical examination, it is recommended to conduct a general examination, examining the skin of the face, torso and extremities.
Strength of recommendation level I (level of evidence certainty C).
During the physical examination, it is recommended to measure height (m) and weight (kg) and determine the body mass index.
Strength of recommendation level I (level of evidence certainty C).
Comments. Body mass index is calculated using the formula - “weight (kg)/height (m)2”.
During the physical examination, it is recommended to auscultate the heart and lungs, palpate the pulse on the radial arteries and arteries of the dorsum of the feet, measure Korotkoff blood pressure with the patient lying, sitting and standing, count heart rate and pulse rate, auscultate the projection points of the carotid arteries, abdominal aorta, iliac arteries, palpate the abdomen, parasternal points and intercostal spaces.
Strength of recommendation level I (level of evidence certainty C).

2.3 Laboratory diagnostics.

Only a few laboratory tests have independent prognostic value in stable CAD. The most important parameter is the lipid spectrum of the blood. Other laboratory tests of blood and urine allow us to identify concomitant diseases and syndromes (thyroid dysfunction, diabetes mellitus, heart failure, anemia, erythremia, thrombocytosis, thrombocytopenia), which worsen the prognosis of coronary artery disease and require consideration when selecting drug therapy and when possibly referring the patient for surgery treatment.
It is recommended that all patients undergo a complete blood count, measuring hemoglobin, red blood cell and white blood cell levels.

When there is a clinical basis, screening for type 2 diabetes is recommended to begin with measuring the level of glycosylated hemoglobin in the blood and the level of fasting blood glucose. If the results are inconclusive, an additional oral glucose tolerance test is recommended.

It is recommended that all patients undergo a blood creatinine level test with an assessment of renal function based on creatinine clearance.
Strength of recommendation level I (level of evidence B).
All patients are recommended to undergo a fasting blood lipid profile, including an assessment of low-density lipoprotein cholesterol (LDL-C).

Comments. Dyslipoproteinemia - a violation of the ratio of the main classes of lipids in plasma - is the leading risk factor for atherosclerosis. Low-density and very low-density lipoproteins are considered protaterogenic, while high-density lipoproteins are an antiatherogenic factor. With a very high level of LDL cholesterol in the blood, IHD develops even in young people. Low levels of high-density lipoprotein cholesterol are an unfavorable prognostic factor. A high level of blood triglycerides is considered a significant predictor of cardiovascular complications.
When clinically warranted, thyroid function screening is recommended to detect thyroid disease.

In patients with suspected heart failure, testing the level of N-terminal fragment of brain natriuretic peptide in the blood is recommended.
Strength of recommendation level IIa (level of evidence C);
In case of clinical instability or if ACS is suspected, repeated measurement of blood troponin levels using a high- or ultra-high-sensitive method is recommended to exclude myocardial necrosis.
Strength of Recommendation Level I (Level of Evidence A);
In patients complaining of symptoms of myopathy while taking statins, it is recommended to study the activity of blood creatine kinase.
Strength of recommendation level I (level of evidence C);
When repeating studies in all patients diagnosed with stable coronary artery disease, it is recommended to conduct annual monitoring of lipid profile, creatinine and glucose metabolism.
Recommendation Strength I (Evidence Level C).

2.4 Instrumental diagnostics.

Electrocardiographic study.
All patients with suspected coronary artery disease, when visiting a doctor, are recommended to perform electrocardiography (ECG) at rest and interpret the electrocardiogram.
Recommendation strength level I (evidence level C) ;
It is recommended that all patients during or immediately after an attack of chest pain that suggests unstable coronary heart disease be recorded with a resting ECG.
If vasospastic angina is suspected, it is recommended to record an ECG during an attack of chest pain.
Recommendation Strength I (Evidence Level C);
Comments. In uncomplicated stable coronary artery disease outside of exercise, specific ECG signs of myocardial ischemia are usually absent. The only specific sign of ischemic heart disease on a resting ECG is large-focal cicatricial changes in the myocardium after an MI. Isolated changes in the T wave, as a rule, are not very specific and require comparison with the clinical picture of the disease and data from other studies. Registration of an ECG during a painful attack in the chest is much more important. If there are no changes in the ECG during pain, the likelihood of ischemic heart disease in such patients is low, although it is not completely excluded. The appearance of any ECG changes during a painful attack or immediately after it significantly increases the likelihood of coronary artery disease. Ischemic ECG changes in several leads at once are an unfavorable prognostic sign. In patients with an initially altered ECG due to post-infarction cardiosclerosis, ECG dynamics during an attack of even typical angina may be absent, low-specific, or false (decreased amplitude and reversal of initially negative T waves). It should be remembered that against the background of intraventricular blockades, ECG registration during a painful attack can also be uninformative. In such cases, the doctor makes a decision on the nature of the attack and treatment tactics based on the accompanying clinical symptoms.
Echocardiographic study.
A transthoracic echocardiogram (EchoCG) at rest is recommended in all patients with suspected stable CAD and in those with previously proven stable CAD.
Strength of recommendation level I (level of evidence B).
Comments. The main purpose of echocardiography at rest is the differential diagnosis of angina pectoris with non-coronary chest pain due to aortic valve defects, pericarditis, aneurysms of the ascending aorta, hypertrophic cardiomyopathy, mitral valve prolapse and other diseases. In addition, echocardiography is the main way to identify and stratify myocardial hypertrophy, local and general left ventricular dysfunction.
A resting transthoracic echocardiogram (EchoCG) is performed to:
ruling out other causes of chest pain;
detection of local disturbances in the mobility of the walls of the left ventricle of the heart;
measurement of left ventricular ejection fraction (LVEF) and subsequent CV risk stratification;
assessment of left ventricular diastolic function.
Ultrasound examination of the carotid arteries.
Ultrasound examination of the carotid arteries in stable coronary artery disease is recommended to identify atherosclerosis of the carotid arteries as an additional risk factor for cardiovascular disease.

Comments. The detection of multiple hemodynamically significant stenoses in the carotid arteries forces us to reclassify the risk of cardiovascular complications as high, even with moderate clinical symptoms.
X-ray examination in stable ischemic heart disease.
At the diagnostic stage, chest radiography is recommended for patients with atypical symptoms of coronary artery disease or to exclude pulmonary disease.
Recommendation Strength I (Evidence Level C).
At the diagnostic stage, and during follow-up, chest radiography is recommended if HF is suspected.
Level of Recommendation Strength IIa (Level of Evidence C).
A comment. A chest x-ray is most informative in persons with post-infarction cardiosclerosis, heart defects, pericarditis and other causes of concomitant heart failure, as well as in cases of suspected aneurysm of the ascending aortic arch. In such patients, radiographs can assess the enlargement of the heart and aortic arch, the presence and severity of intrapulmonary hemodynamic disorders (venous stagnation, pulmonary arterial hypertension). For atypical chest pain, radiographic examination can be useful in identifying diseases of the musculoskeletal system during the differential diagnosis.
ECG monitoring.
ECG monitoring is recommended for patients with proven stable coronary artery disease and suspected concomitant arrhythmia.
Recommendation Strength I (Evidence Level C).
ECG monitoring is recommended at the diagnostic stage in patients with suspected vasospastic angina.
Level of Recommendation Strength IIa (Level of Evidence C).
ECG monitoring is recommended at the diagnostic stage if it is impossible to perform stress tests due to concomitant diseases (diseases of the musculoskeletal system, intermittent claudication, a tendency to a pronounced increase in blood pressure during dynamic physical activity, detraining, respiratory failure).
Level of Recommendation Strength IIa (Level of Evidence C).
A comment. The method allows you to determine the incidence and duration of painful and painless myocardial ischemia. Sensitivity of ECG monitoring in the diagnosis of coronary artery disease: 44-81%, specificity: 61-85%. This diagnostic method is less informative for identifying transient myocardial ischemia than exercise testing. Prognostically unfavorable findings during ECG monitoring: 1) long total duration of myocardial ischemia; 2) episodes of ventricular arrhythmias during myocardial ischemia; 3) myocardial ischemia at low heart rate (< 70 уд. /мин). Выявление суммарной продолжительности ишемии миокарда 60 мин в сутки служит веским основанием для направления пациента на коронароангиографию (КАГ) и последующую реваскуляризацию миокарда, поскольку говорит о тяжелом поражении КА .
Assessment of primary examination data and pre-test probability of coronary artery disease.
It is recommended, when examining individuals without a previously established diagnosis of coronary artery disease, to estimate the pre-test probability (PTP) of this diagnosis based on data obtained during anamnesis, physical and laboratory examination, resting ECG, echocardiography and chest X-ray examination, ultrasound examination of the carotid arteries according to indications. and ambulatory ECG monitoring.
Recommendation Strength I (Evidence Level C).
Comments. After the initial studies, the doctor builds a plan for further examination and treatment of the patient, based on the received primary data and the PTT diagnosis of stable IHD (Table 2).
Table 2. Pretest probability of diagnosis of stable coronary heart disease depending on the nature of chest pain.

Age, years	Typical angina		Atypical angina		Non-coronary pain
	men	women	men	women	men	women
30-39	59%	28%	29%	10%	18%	5%
40-49	69%	37%	38%	14%	25%	8%
50-59	77%	47%	49%	20%	34%	12%
60-69	84%	58%	59%	28%	44%	17%
70-79	89%	68%	69%	37%	54%	24%
80	93%	76%	78%	47%	65%	32%

It is recommended that in patients with a PTT diagnosis of coronary artery disease of 65%, further studies to confirm the diagnosis should not be carried out, but rather, CV risk stratification and treatment should be started.
Recommendation Strength I (Evidence Level C).
Recommended. Patients with PTV diagnosis of IHD< 15% направить на обследование для выявления функционального заболевание сердца или некардиальных причин клинических симптомов.
Recommendation Strength I (Evidence Level C).
It is recommended that patients with an intermediate PTT diagnosis of CAD (15-65%) be referred for additional non-invasive stress and imaging diagnostic studies.
Recommendation Strength I (Evidence Level C).
Registration of ECG during exercise tests.
Stress ECG with exercise is recommended as an initial method for establishing a diagnosis of angina syndrome against the background of intermediate PTT for detection of coronary artery disease (15-65%) not taking anti-ischemic drugs.
Recommendation Strength I (Evidence Level B).
Comments. An exercise stress ECG is not performed if the patient is unable to perform physical activity or if the initial ECG changes make it impossible to evaluate.
Exercise stress ECG is recommended in patients diagnosed with and receiving treatment for CAD to assess its effect on symptoms and myocardial ischemia.
Level of Recommendation Strength IIa (Level of Evidence C) ;
Exercise stress ECG is not recommended in patients receiving cardiac glycosides or with ST segment depression on the resting ECG of 0.1 mV.
Strength of Recommendation Level III (Level of Evidence C).
A comment. Typically the stress test is a bicycle ergometry test or a treadmill test. The sensitivity of stress ECG with physical activity in the diagnosis of coronary artery disease is 40-50%, specificity is 85-90%. The walking test (treadmill test) is more physiological and is more often used to verify the functional class of patients with coronary artery disease. Bicycle ergometry is more informative in identifying ischemic heart disease in unclear cases, but it requires the patient to have at least basic cycling skills; it is more difficult to perform in elderly patients and with concomitant obesity. The prevalence of transesophageal atrial electrical stimulation in the routine diagnosis of coronary artery disease is lower, although this method is comparable in information content to bicycle ergometry (VEM) and treadmill test. The method is performed for the same indications, but is the means of choice if the patient is unable to perform other stress tests due to non-cardiac factors (diseases of the musculoskeletal system, intermittent claudication, a tendency to a pronounced increase in blood pressure during dynamic physical activity, detraining, respiratory failure). .
Stress methods for imaging myocardial perfusion.
Stress methods for imaging myocardial perfusion include:
Stress echocardiography with physical activity.
Stress echocardiography with pharmacological load (dobutamine or vasodilator).
Stress echocardiography with a vasodilator.
Myocardial perfusion scintigraphy with physical activity.
Stress echocardiography is one of the most popular and highly informative methods for non-invasive diagnosis of coronary artery disease. The method is based on visual detection of local LV dysfunction, as the equivalent of ischemia, during physical activity or a pharmacological test. Stress echocardiography is superior to conventional stress ECG in diagnostic value, has greater sensitivity (80-85%) and specificity (84-86%) in the diagnosis of coronary artery disease. The method allows not only to provide evidence-based verification of ischemia, but also to preliminarily determine symptom-related coronary artery disease based on the location of transient LV dysfunction. If technically possible.
Carrying out stress echocardiography with physical activity is indicated for all patients with proven coronary artery disease to verify symptom-related coronary artery disease, as well as in case of questionable results of a conventional stress test during the initial diagnosis.
Level of Recommendation Strength IIa (Level of Evidence C).
If microvascular angina is suspected, stress echocardiography with exercise or dobutamine is recommended to verify local hypokinesis of the LV wall, which occurs simultaneously with angina and ECG changes.
Level of Strength of Recommendation IIa (Level of Evidence C);
If microvascular angina is suspected, it is recommended to perform echocardiography with Doppler examination of the left coronary artery with measurement of diastolic coronary blood flow after intravenous administration of adenosine to study the coronary blood flow reserve.
Level of Strength of Recommendation IIb (Level of Evidence C).
A comment. Myocardial perfusion scintigraphy (single photon emission computed tomography and positron emission tomography) is a sensitive and highly specific imaging method with high prognostic significance. The combination of scintigraphy with physical activity or pharmacological tests (dosed intravenous administration of dobutamine, dipyridamole) greatly increases the value of the results obtained. The positron emission tomography method allows one to estimate minute blood flow per unit of myocardial mass and is especially informative in the diagnosis of microvascular angina.
Carrying out a scintigraphic study of myocardial perfusion in combination with physical activity is recommended for stable coronary artery disease for verification of symptom-related coronary artery disease and for assessing the prognosis of the disease.
Level of Strength of Recommendation IIa (Level of Evidence C);
Carrying out a scintigraphic study of myocardial perfusion in combination with a pharmacological test (intravenous administration of dobutamine or dipyridamole) is recommended for stable ischemic heart disease to verify symptom-related coronary artery disease and to assess the prognosis of the disease when the patient is unable to perform standard physical activity (due to detraining, musculoskeletal diseases). apparatus and/or lower extremities, etc.).

Conducting a positron emission tomographic study of myocardial perfusion is recommended when diagnosing microvascular angina.
Level of Recommendation Strength IIb (Level of Evidence C);
Stress imaging is recommended as the initial method for diagnosing stable CAD when PTT is 66-85% or when LVEF is present.< 50% у лиц без типичной стенокардии .
Recommendation Strength I (Evidence Level B);
Stress imaging is recommended as the initial diagnostic modality if features of the resting ECG preclude its interpretation during exercise.
Recommendation Strength I (Evidence Level B).
Exercise-based imaging modalities are recommended over pharmacological stress-based imaging modalities.
Recommendation Strength I (Evidence Level C);
Stress imaging is recommended as the preferred method in individuals with symptoms of CAD who have undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).
Level of Strength of Recommendation IIa (Level of Evidence B);
The stress imaging method is recommended as the preferred method for assessing the functional significance of stenoses of intermediate severity according to CAG data.
Level of Recommendation Strength IIa (Level of Evidence B) ;
In patients with stable coronary artery disease with a pacemaker, stress echocardiography or single-photon emission computed tomography is recommended.

Stress imaging for CV risk stratification is recommended in patients with nondiagnostic exercise stress ECG results.

CV risk stratification using stress ECG or stress imaging is recommended in patients with stable CAD when there is a significant change in the incidence and severity of symptoms.
Strength of recommendation level I (Level of certainty of evidence B).
With concomitant blockade of the left bundle branch, stress echocardiography or single-photon emission computed tomography of the myocardium with a pharmacological load is recommended for stratification by risk of cardiovascular disease.
Level of strength of recommendation IIa (Level of evidence B).
Invasive studies in stable ischemic heart disease.
Invasive coronary angiography (CAG) has traditionally been the “gold standard” for diagnosing coronary heart disease and stratifying the risk of complications.
In cases of proven coronary artery disease, coronary angiography is recommended for CV risk stratification in persons with severe stable angina (FC III-IV) or with clinical signs of high risk of CV events, especially when symptoms are difficult to treat.
Recommendation Strength I (Evidence Level C).

Coronary heart disease is a common cardiovascular pathology that occurs as a result of impaired blood supply to the myocardium.

Coronary heart disease is the most common among all cardiovascular diseases in Russia.

In 28% of cases, it is precisely this that causes adults to go to medical institutions.

Moreover, only half of patients with coronary artery disease know that they have this pathology and receive treatment; in all other cases, ischemia remains unrecognized, and its first manifestation is acute coronary syndrome or myocardial infarction.

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Diagnoses according to ICD-10

1. I20.1 Angina pectoris with documented spasm
2. I20.8 Other forms of angina
3. I20.9 Angina pectoris, unspecified
4. I25 Chronic ischemic heart disease

Coronary heart disease is damage to the heart muscle associated with impaired blood flow through the coronary arteries.

This violation, in turn, can be organic (irreversible) and functional (transient).

In the first case, the main cause of IHD is stenotic atherosclerosis. Factors of functional damage to the coronary arteries are spasms, transient platelet aggregation, and intravascular thrombosis.

The concept of “coronary heart disease” includes both acute transient (unstable) and chronic (stable) conditions.

Most often, the main causes of the development of IHD are stable anatomical atherosclerotic and/or functional stenosis of epicardial vessels and/or microvascular dysfunction.

The main risk factors for coronary heart disease:

1. High blood cholesterol levels.
2. Diabetes.
3. Arterial hypertension.
4. Sedentary lifestyle.
5. Tobacco smoking.
6. Overweight, obesity.

✔ Distribution of patients with coronary artery disease according to risk level based on non-invasive diagnostic methods, download the table in the Consilium System.

Download table

In addition, risk factors for coronary heart disease that cannot be influenced are:

• being male;
• age;
• burdened heredity.

In addition, there are social risk factors that increase the incidence of CHD among the population of developing countries:

• urbanization;
• industrialization;
• economic backwardness of the population.

Ischemia in humans develops when the need of the heart muscle for oxygen exceeds the ability to deliver it with blood through the coronary arteries.

The mechanisms of development of IHD are:

• decreased coronary reserve (the ability to increase coronary blood flow with increased metabolic needs of the myocardium);
• primary decrease in coronary blood flow.

The oxygen demand of the heart muscle is determined by three factors:

1. Tension of the walls of the left ventricle.
2. Myocardial contractility.

The higher the value of each of these indicators, the higher the myocardial oxygen demand.

The amount of coronary blood flow depends on:

• coronary artery resistance;
• heart rate;
• perfusion pressure (the so-called difference between diastolic pressure in the aorta and the same in the left ventricle).

Angina pectoris

Angina pectoris is the most common form of cardiac ischemia. Its frequency increases with age in both men and women. The annual mortality rate from IHD is about 1.2-2.4%, and 0.6-1.4% of patients die every year from fatal cardiovascular complications, while the percentage of non-fatal myocardial infarction is 0.6-2. 7 per year.

However, in subpopulations with various additional risk factors, these values ​​may be different.

Patients diagnosed with stable angina die from ischemia 2 times more often than patients without this diagnosis. There are currently no epidemiological data on microvascular and vasospastic angina.

Revascularization of the heart muscle in order to relieve attacks of angina, reduce its functional class and improve the quality of life is recommended for all patients with angina in the presence of coronary stenosis >50 percent with documented myocardial ischemia or fractional flow reserve (FFR) ≤ 0.80 in combination with angina (and/ or its equivalents), refractory to drug therapy.

It must be said that for coronary artery stenoses less than 90%, additional tests are required to prove their hemodynamic significance (documented myocardial ischemia, including stress testing with myocardial imaging or determination of FFR).

Myocardial revascularization to improve the prognosis of the underlying pathology is indicated for all patients with a large area of ​​ischemia (>10% in the left ventricle), as well as for all patients with a single preserved artery with a stenosis of >50 percent.

Surgery on the coronary arteries improves the prognosis of patients with a large area of ​​ischemia.

A large area of ​​damage to the heart muscle can be judged by the presence of a hemodynamically important lesion of a large coronary artery:

• trunk of the left coronary artery;
• proximal anterior descending artery;
• two- or three-vessel disease with decreased left ventricular function;
• the only surviving coronary vessel.

When choosing a method, it is necessary to consider factors such as:

1. Anatomical features of coronary artery lesions.
2. Concomitant diseases and possible risks.
3. The patient's consent to a specific method of surgical treatment.

In the event that both ABS and PCI with stenting are possible, and the patient agrees to any type of intervention, the choice of technique is determined by the anatomical features of the coronary lesion.

Coronary heart disease: treatment

Conservative treatment of stable cardiac ischemia is based on the elimination of risk factors that can be influenced, as well as complex drug treatment. The patient should be informed of all risks and treatment strategies.

When collecting anamnesis and examination, it is necessary to pay attention to concomitant pathologies, especially when it comes to arterial hypertension, diabetes mellitus and hypercholesterolemia.

Eliminating risk factors is a complex and indefinitely long task. The most important role here is played by informing and educating the patient, since only an informed and trained patient will strictly follow medical recommendations and will be able to make important decisions in the future depending on the symptoms.

• discuss with the patient the prospects for both drug treatment and surgical intervention;
• stipulate the need and frequency of instrumental and laboratory tests;
• talk about the most common symptoms of unstable angina, AMI, emphasize the importance of promptly contacting specialists if they occur;
• give clear recommendations for maintaining a healthy lifestyle, emphasizing the importance of treating concomitant diseases.

Drug therapy is aimed at eliminating the clinical manifestations of coronary artery disease, as well as preventing complications from the heart and blood vessels. It is recommended that the patient be prescribed at least one drug to eliminate the symptoms of angina pectoris in combination with preventive drugs.

Indications for conducting research methods are indicated in accordance with classes: class I - research is useful and effective; IIA - data on usefulness are inconsistent, but there is more evidence in favor of the effectiveness of the study; IIB - data on usefulness are contradictory, but the benefits of the study are less obvious; III - research is useless.

The degree of evidence is characterized by three levels: level A - there are several randomized clinical trials or meta-analyses; level B - data obtained from a single randomized trial or from non-randomized studies; level C—recommendations are based on expert agreement.

• with stable angina or other symptoms associated with coronary artery disease, such as shortness of breath;
• with established coronary artery disease, currently asymptomatic due to treatment;
• patients in whom symptoms are noted for the first time, but it is established that the patient has a chronic stable disease (for example, from the anamnesis it is revealed that similar symptoms have been present for several months).

Thus, stable coronary artery disease includes different phases of the disease, with the exception of the situation when clinical manifestations are determined by coronary artery thrombosis (acute coronary syndrome).

In stable CAD, symptoms during exercise or stress are associated with stenosis of the left main coronary artery >50% or stenosis of one or more large arteries >70%. This edition of the Guidelines discusses diagnostic and prognostic algorithms not only for such stenoses, but also for microvascular dysfunction and spasm of the coronary arteries.

Definitions and pathophysiology

Stable ischemic heart disease is characterized by a discrepancy between oxygen demand and oxygen delivery, leading to myocardial ischemia, which is usually provoked by physical or emotional stress, but sometimes occurs spontaneously.

Episodes of myocardial ischemia are associated with chest discomfort (angina). Stable coronary artery disease also includes an asymptomatic phase of the disease, which can be interrupted by the development of acute coronary syndrome.

Various clinical manifestations of stable CAD are associated with different mechanisms, including:

• obstruction of the epicardial arteries,
• local or diffuse spasm of the artery without stable stenosis or in the presence of atherosclerotic plaque,
• microvascular dysfunction,
• left ventricular dysfunction associated with myocardial infarction or ischemic cardiomyopathy (myocardial hibernation).

These mechanisms can be combined in one patient.

Natural history and prognosis

In a population of patients with stable CAD, individual prognosis may vary depending on clinical, functional and anatomical characteristics.

There is a need to identify patients with more severe disease who may have a better prognosis with aggressive intervention, including revascularization. On the other hand, it is important to identify patients with mild forms of the disease and a good prognosis, in whom unnecessary invasive interventions and revascularization should be avoided.

Diagnosis

Diagnosis includes clinical assessment, instrumental studies and imaging of the coronary arteries. Studies can be used to confirm the diagnosis in patients with suspected ischemic heart disease, identify or exclude concomitant conditions, risk stratification, and evaluate the effectiveness of therapy.

Symptoms

When assessing chest pain, the Diamond A.G. classification is used. (1983), according to which typical, atypical angina and non-cardiac pain are distinguished. An objective examination of a patient with suspected angina pectoris reveals anemia, arterial hypertension, valvular lesions, hypertrophic obstructive cardiomyopathy, and rhythm disturbances.

It is necessary to assess body mass index, identify vascular pathology (pulse in the peripheral arteries, murmur in the carotid and femoral arteries), and determine comorbid conditions such as thyroid disease, kidney disease, diabetes mellitus.

Non-invasive research methods

The optimal use of noninvasive testing is based on the assessment of the pretest probability of CAD. Once diagnosed, management depends on the severity of symptoms, risk, and patient preference. A choice between drug therapy and revascularization and a choice of revascularization method are necessary.

Basic studies in patients with suspected coronary artery disease include standard biochemical tests, ECG, daily ECG monitoring (if symptoms are suspected of being associated with paroxysmal arrhythmia), echocardiography and, in some patients, chest radiography. These tests can be performed on an outpatient basis.

EchoCG provides information about the structure and function of the heart. In the presence of angina, it is necessary to exclude aortic and subaortic stenosis. Global contractility is a prognostic factor in patients with coronary artery disease. EchoCG is especially important in patients with heart murmurs, previous myocardial infarction, and symptoms of heart failure.

Thus, transthoracic echocardiography is indicated for all patients for:

• ruling out an alternative cause of angina;
• identifying violations of local contractility;
• ejection fraction (EF) measurements;
• assessment of left ventricular diastolic function (Class I, level of evidence B).

There are no indications for repeat studies in patients with uncomplicated coronary artery disease in the absence of changes in clinical condition.

Ultrasound examination of the carotid arteries necessary to determine the thickness of the intima-media complex and/or atherosclerotic plaque in patients with suspected ischemic heart disease (Class IIA, level of evidence C). Detection of changes is an indication for preventive therapy and increases the pretest probability of CAD.

Daily ECG monitoring rarely provides additional information compared to ECG stress tests. The study is important in patients with stable angina and suspected rhythm disturbances (Class I, level of evidence C) and in patients with suspected vasospastic angina (Class IIA, level of evidence C).

X-ray examination indicated in patients with atypical symptoms and suspected pulmonary disease (Class I, level of evidence C) and suspected heart failure (Class IIA, level of evidence C).

A step-by-step approach to diagnosing coronary artery disease

Step 2 is the use of non-invasive methods to diagnose coronary artery disease or non-obstructive atherosclerosis in patients with an average likelihood of coronary artery disease. Once the diagnosis is established, optimal drug therapy and stratification of the risk of cardiovascular events are necessary.

Step 3—noninvasive tests to select patients who would benefit more from invasive intervention and revascularization. Depending on the severity of symptoms, early coronary angiography (CAG) may be performed, bypassing steps 2 and 3.

Pretest probability is estimated taking into account age, gender and symptoms (table).

Principles of using non-invasive tests

The sensitivity and specificity of non-invasive imaging tests is 85%, therefore 15% of results are false positives or false negatives. In this regard, testing of patients with a low (less than 15%) and high (more than 85%) pretest probability of CAD is not recommended.

Stress ECG tests have low sensitivity (50%) and high specificity (85-90%), therefore tests are not recommended for diagnosis in a group with a high probability of coronary artery disease. In this group of patients, the purpose of performing ECG stress tests is to assess the prognosis (risk stratification).

Patients with low EF (less than 50%) and typical angina are recommended to undergo coronary angiography without non-invasive tests, as they have a very high risk of cardiovascular events.

Patients with a very low probability of CAD (less than 15%) need to exclude other causes of pain. With an average probability (15-85%), non-invasive testing is indicated. In patients with a high probability (more than 85%), testing is necessary for risk stratification, but in severe angina, it is advisable to perform coronary angiography without non-invasive tests.

The very high negative predictive value of computed tomography (CT) makes the method important for patients with lower average risk values ​​(15-50%).

Stress ECG

VEM or treadmill is indicated at a pretest probability of 15-65%. Diagnostic testing is performed when anti-ischemic drugs are discontinued. The sensitivity of the test is 45-50%, specificity 85-90%.

The study is not indicated for left bundle branch block, WPW syndrome, or the presence of a pacemaker due to the inability to interpret changes in the ST segment.

False-positive results are observed with ECG changes associated with left ventricular hypertrophy, electrolyte disturbances, intraventricular conduction disturbances, atrial fibrillation, and digitalis use. In women, the sensitivity and specificity of tests is lower.

In some patients, testing is not informative due to failure to achieve submaximal heart rate in the absence of ischemic symptoms, with restrictions associated with orthopedic and other problems. An alternative for these patients is pharmacologically guided imaging.

• for the diagnosis of coronary artery disease in patients with angina pectoris and an average probability of coronary artery disease (15-65%), not receiving anti-ischemic drugs, who can perform physical activity and do not have ECG changes that do not allow interpretation of ischemic changes (Class I, level of evidence B);
• to evaluate the effectiveness of treatment in patients receiving anti-ischemic therapy (Class IIA, level C).

Stress echocardiography and myocardial perfusion scintigraphy

Stress echocardiography is performed using physical activity (VEM or treadmill) or pharmacological drugs. Exercise is more physiological, but pharmacological exercise is preferred when resting contractility is impaired (dobutamine to assess viable myocardium) or in patients unable to exercise.

Indications for stress echocardiography:

• for diagnosing ischemic heart disease in patients with a pretest probability of 66-85% or with EF<50% у больных без стенокардии (Класс I, уровень доказанности В);
• for the diagnosis of ischemia in patients with ECG changes at rest that do not allow interpretation of the ECG during stress tests (Class I, level of evidence B);
• exercise testing for stress Echocardiography is preferable to pharmacological tests (Class I, level of evidence C);
• in symptomatic patients undergoing percutaneous intervention (PCI) or coronary artery bypass grafting (CABG) (Class IIA, level of evidence B);
• to assess the functional significance of moderate stenoses identified by coronary angiography (Class IIA, level of evidence B).

Perfusion scintigraphy (BREST) ​​with technetium (99mTc) can detect myocardial hypoperfusion during exercise compared with perfusion at rest. It is possible to provoke ischemia with physical activity or medication with the use of dobutamine and adenosine.

Research with thallium (201T1) is associated with a higher radiation load and is currently used less frequently. Indications for perfusion scintigraphy are similar to those for stress echocardiography.

Positron emission tomography (PET) has advantages over BREST in terms of image quality, but is less accessible.

Non-invasive methods for assessing coronary anatomy

CT can be performed without administration of contrast (calcium deposition in the coronary arteries is determined) or after intravenous administration of an iodinated contrast agent.

Calcium deposition is a consequence of coronary atherosclerosis, except in patients with renal failure. When determining coronary calcium, the Agatston index is used. The amount of calcium correlates with the severity of atherosclerosis, but the correlation with the degree of stenosis is poor.

Coronary CT angiography with the introduction of a contrast agent allows you to evaluate the lumen of blood vessels. Conditions are the patient's ability to hold his breath, absence of obesity, sinus rhythm, heart rate less than 65 per minute, absence of severe calcification (Agatston index< 400).

Specificity decreases with increasing coronary calcium. CT angiography is not advisable if the Agatston index is > 400. The diagnostic value of the method is available in patients with the lower limit of the average probability of coronary artery disease.

Coronary angiography

CAG is rarely necessary for diagnosis in stable patients. The study is indicated if the patient cannot undergo stress imaging studies, with an EF less than 50% and typical angina, or in persons of special professions.

CAG is indicated after non-invasive risk stratification in the high-risk group to determine indications for revascularization. In patients with a high pretest probability and severe angina, early coronary angiography is indicated without previous non-invasive tests.

CAG should not be performed in patients with angina who refuse PCI or CABG or in whom revascularization would not improve functional status and quality of life.

Microvascular angina

Primary microvascular angina should be suspected in patients with typical angina, positive results of stress ECG tests in the absence of stenotic lesions of the epicardial coronary arteries.

Tests required to diagnose microvascular angina:

• stress echocardiography with exercise or dobutamine to detect disturbances of local contractility during an attack of angina and changes in the ST segment (Class IIA, level of evidence C);
• transthoracic Doppler echocardiography of the anterior descending artery with measurement of diastolic coronary blood flow after intravenous administration of adenosine and at rest for non-invasive assessment of coronary reserve (Class IIB, level of evidence C);
• CAG with intracoronary administration of acetylcholine and adenosine in normal coronary arteries to assess coronary reserve and determine microvascular and epicardial vasospasm (Class IIB, level of evidence C).

Vasospastic angina

Diagnosis requires recording an ECG during an attack of angina. CAG is indicated to evaluate the condition of the coronary arteries (Class I, level of evidence C). Daily ECG monitoring to detect ST segment elevation in the absence of an increase in heart rate (Class IIA, level of evidence C) and CAG with intracoronary administration of acetylcholine or ergonovine to identify coronary spasm (Class IIA, level of evidence C).

For quotation: Soboleva G.N., Karpov Yu.A. Recommendations of the European Society of Cardiology on stable coronary artery disease 2013: microvascular angina // Breast Cancer. 2013. No. 27. S. 1294

In September 2013, new recommendations for the diagnosis and treatment of stable coronary artery disease (CAD) were introduced. Among the many changes in recommendations, angina pectoris with intact coronary arteries (CA), or microvascular angina, has received increased attention. The range of clinicopathological correlations between symptoms and the nature of changes in the coronary artery during angina is quite wide and varies from typical manifestations of angina caused by stenosing lesions of the coronary artery and transient myocardial ischemia, to pain syndrome atypical for angina with unchanged coronary arteries. This ranges from a pain syndrome atypical for angina against the background of significant stenoses in the coronary artery, which ultimately takes the form of a diagnosis of “angina pectoris,” to a typical clinical picture of the disease against the background of unchanged coronary artery disease, which is proposed to be identified as “microvascular angina” (MVS) in the 2013 Recommendations for stable angina, or previously - cardiac syndrome X (CSX).

The definition of “CCX” was first used in 1973 by Dr. H.G. Kemp, who drew attention to the research of Canadian scientists R. Arbogast and M.G. Bou-rassa. Pain syndrome in this group of patients may differ in the following characteristics:
1) pain can cover a small part of the left half of the chest, last from several hours to several days and cannot be relieved by taking nitroglycerin;
2) pain may have typical characteristics of an anginal attack in terms of location and duration, but may occur at rest (atypical angina caused by vasospasm);
3) it is possible to manifest a pain syndrome with typical characteristics of an anginal attack, but longer in time without a clear connection with physical activity and a negative result of stress tests, which corresponds to the clinical picture of MWS.
Diagnosis and determination of treatment tactics in patients with MWS are a complex task. In a significant proportion of patients (approximately 50% of women and 20% of men) with angina pectoris, coronary angiography (CAG) does not reveal atherosclerosis of the epicardial arteries, which indicates a dysfunction (coronary reserve) of microvessels. Data from the National Heart, Lung, and Blood Institute's Women's Ischemia Syndrome Evaluation (WISE) study demonstrated a 2.5% annual risk of adverse cardiovascular events in this group of patients, including death, myocardial infarction, stroke, and heart failure. Results of a 20-year follow-up of 17,435 patients in Denmark with intact coronary arteries and non-obstructive diffuse coronary artery disease with angina showed a 52 and 85% increased risk of major cardiovascular events (cardiovascular mortality, hospitalization for myocardial infarction, heart failure, stroke) and 29 and 52% increased risk of total mortality, respectively, in these groups, without significant differences by gender.
Despite the lack of a universal definition of MBC, the main manifestations of the disease correspond to the presence of a triad of signs:
1) typical angina caused by exercise (in combination or in the absence of rest angina and shortness of breath);
2) the presence of signs of myocardial ischemia according to ECG, Holter ECG monitoring, stress tests in the absence of other diseases of the cardiovascular system;
3) unchanged or slightly changed coronary arteries (stenoses<50%) . Наиболее чувствительным методом диагностики ишемии миокарда у этих больных является применение фармакологических тестов или ВЭМ-теста в сочетании с однофотонной эмиссионной компьютерной томографией миокарда при введении 99mTc-МИБИ (аналог таллия-201), позволяющего визуализировать дефекты перфузии миокарда как результат нарушенного коронарного резерва в ответ на повышенные метаболические потребности миокарда. Приступы стенокардии могут возникать достаточно часто - несколько раз в неделю, но при этом иметь стабильный характер. Таким образом, МВС является формой хронической стенокардии и по МКБ-10 относится к коду 120.8 «Другие формы стенокардии». Диагноз формулируется в зависимости от функционального класса стенокардии, например «ИБС при неизмененных коронарных артериях. Стенокардия ФК II. (Микроваскулярная стенокардия)».
The main cause of MVA is coronary microvascular dysfunction, defined as the abnormal response of the coronary microcirculation to vasoconstrictor and vasodilator stimuli. Figure 1 shows the main mechanisms and signaling pathways for the regulation of coronary blood flow. Endothelial dysfunction, hyperreactivity of smooth muscle cells, and increased activity of the sympathetic nervous system have been discussed as the main causes of microvascular dysfunction. Estrogen deficiency may contribute to the development of CSC through endothelial dysfunction (ED) in postmenopausal women. Known traditional risk factors for atherosclerosis, such as dyslipidemia, smoking, obesity, and carbohydrate metabolism disorders, can also influence the development of coronary endothelial dysfunction with the subsequent development of AVS.
Coronary reserve, defined as the ratio of myocardial blood flow in the hyperemic phase with basal blood flow, decreases when basal blood flow is increased or reduced during the hyperemic phase. Basal blood flow correlates with hemodynamic parameters (blood pressure, neurohumoral parameters, myocardial metabolism, heart rate - HR). Recently, evidence has been obtained of the presence of delayed reuptake of norepinephrine at synapses in women, which may explain the specificity of MBC for women and impaired autonomic regulation of microvascular tone with a decrease in coronary reserve. In contrast, the hyperemic response is regulated by endothelium-dependent and endothelium-independent responses. The mechanisms causing damage to hyperemic myocardial blood flow in patients with MWS are currently not specified: some patients demonstrate endothelial dysfunction, others demonstrate an abnormality of endothelium-independent vasodilatory reactions, in particular a defect in adenosine metabolism. We were the first to demonstrate a decrease in myocardial perfusion reserve when performing ATP-SPECT of the myocardium (Fig. 2). It is possible to use dipyridamole to assess coronary reserve using transthoracic Doppler ultrasound (Fig. 3), and convincing evidence in favor of reducing coronary reserve has been obtained from studies using cardiac positron emission tomography.
Ischemic changes on the ECG and defects in the uptake of thallium by the myocardium during stress tests are identical in patients with MVS and obstructive atherosclerosis of epicardial coronary arteries, but differ in the absence of hypokinesis zones in MVS, which is due to the small volumes of ischemic foci, their frequent localization in the subendocardial zone, and the rapid washout of anaerobic metabolites and the appearance of zones with compensatory hypercontractility of adjacent myocytes, which significantly limits the possibility of visualizing such zones with impaired contractility. Nevertheless, the compensatory release of adenosine may be sufficient to stimulate the afferent fibers that cause the sensation of pain, which is especially pronounced in conditions of increased pain sensitivity that characterizes patients with MWS.
MBC, as noted above, is established in the presence of angina attacks, documented myocardial ischemia in the absence of hemodynamically significant stenoses in the coronary artery (stenoses ≤50% or intact coronary arteries) and the absence of signs of vasospasm (as is the case with variant Prinzmetal angina). Myocardial ischemia is usually documented by stress tests, such as bicycle ergometry (VEM), treadmill test, or 24-hour Holter monitoring ECG (HM-ECG) by detecting horizontal depression of the ST segment more than 1 mm from the J point on the ECG. The method practiced by doctors to exclude the diagnosis of coronary heart disease by only identifying unchanged coronary arteries according to coronary angiography in patients with chest pain, refusing to conduct additional research methods that most accurately verify myocardial ischemia, should be considered unacceptable, because this leads to underestimation of angina symptoms and failure to prescribe the necessary drug therapy, which worsens the course of the disease and requires repeated hospitalizations. Thus, reliable verification of myocardial ischemia in patients with CSC seems to be a determinant that determines the strategy and tactics of treatment, and therefore the prognosis of life in this group of patients.
Patients with MWS are characterized by low reproducibility of ischemic changes on the ECG during stress tests and virtually no ability to identify zones of hypokinesis according to stress echocardiography, which is due to the development of subendocardial ischemia due to spasm of intramyocardial vessels, in contrast to patients with obstructive atherosclerosis of the epicardial arteries, corresponding transmural ischemia and systolic myocardial dysfunction.
Verification of myocardial ischemia in this group of patients is possible:
1) when visualizing myocardial perfusion defects in stress or pharmacological tests;
2) confirmation by biochemical methods of metabolic disorders in the myocardium.
Due to the labor-intensive nature of the latter technique, the fundamental methods for verifying myocardial ischemia in patients with MWS are:
1. Single-photon emission computed tomography of the heart, combined with a VEM test or a pharmaceutical test. In the first case, upon reaching a submaximal heart rate (HR) or ECG signs of myocardial ischemia during a VEM test, patients are administered intravenously 99mTc-MIBI (99mTc-methoxyisobutyl isonitrile) with an activity of 185-370 mBq, followed 1 hour later by SPECT of the myocardium and assessment perfusion defects. In cases where the exercise test is insufficiently informative or its results are negative, an alternative method for radionuclide studies of myocardial perfusion is a method using a pharmacological test. In this case, the VEM test is replaced by intravenous administration of a pharmaceutical drug (dobutamine, dipyridamole, adenosine). Previously, studies were conducted at the Federal State Budgetary Institution RKNPK of the Ministry of Health of Russia with the administration of acetylcholine intracoronally and 99mTc-MIBI intravenously with the aim of provoking myocardial ischemia caused by endothelial dysfunction. These data were subsequently confirmed in an ACOVA study. This method demonstrated high information content, but was not widely used due to its invasive nature. The use of dobutamine seems inappropriate in patients with MWS, because the expected effects of decreased myocardial contractility due to ischemia will be extremely rare, as in the case of stress echocardiography. Currently, studies conducted at the Federal State Budgetary Institution RKNPK of the Ministry of Health of Russia allow us to recommend in wide clinical practice a method for verifying myocardial ischemia in patients with cardiac arrest - myocardial SPECT, combined with the administration of adenosine triphosphate (ATP) available on the pharmaceutical market of the Russian Federation.
2. Intracoronary administration of adenosine with assessment of blood flow velocity using intravascular ultrasound proves the presence of abnormal blood flow velocity in patients with VS.
3. Abnormal phosphocreatine/ATP ratio in the myocardium in patients with cardiac syndrome according to MR spectroscopy.
4. Subendocardial perfusion defects according to cardiac MRI.
During treatment, an optimal level of risk factors should be achieved in all patients with MWS. The selection of symptomatic therapy is empirical in nature due to the unspecified cause of the disease. The results of clinical studies cannot be generalized due to the lack of uniform selection criteria and the small number of patient samples, imperfect study design and failure to achieve effective treatment for MWS.
Traditional antianginal drugs are prescribed in the first stages of treatment. Short-acting nitrates are recommended to relieve anginal attacks, but they often have no effect. Due to the dominant symptoms of angina pectoris, therapy with β-blockers seems rational, the positive effect of which on eliminating the symptoms of angina pectoris has been proven in several studies; These are the drugs of first choice, especially in patients with obvious signs of increased adrenergic activity (high heart rate at rest or during exercise).
Calcium antagonists and long-acting nitrates have shown mixed results in clinical trials, but their effectiveness is evident when given in addition to beta-blockers in cases of persistent angina. Calcium antagonists may be recommended as first-line drugs in case of variability in the angina threshold. In patients with persistent angina despite optimal antianginal therapy, the following may be suggested. ACE inhibitors (or angiotensin II blockers) can improve microvascular function by neutralizing the vasoconstrictor effect of angiotensin II, especially in patients with arterial hypertension and diabetes mellitus. It is possible to prescribe α-blockers to some patients to suppress increased sympathetic activity, the effect of which on the symptoms of angina pectoris remains unclear. Improvement in exercise tolerance in patients with SWS has been demonstrated during therapy with nicorandil.
Improvement in clinical symptoms was achieved through correction of endothelial function during statin therapy and estrogen replacement therapy. Patients with persistent angina pectoris during therapy with the drugs mentioned above may be offered treatment with xanthine derivatives (aminophylline, bamiphylline) in addition to antianginal drugs to block adenosine receptors. New antianginal drugs - ranolazine and ivabradine - have also demonstrated effectiveness in patients with MWS (Table 1). Finally, in the case of refractory angina, additional interventions (eg, transcutaneous neurostimulation) should be discussed.

Literature
1. 2013 ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. http://eurheartj.oxfordjournals.org/content/early/2013/08/28/eurheartj.eht296
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