Cardiac syndrome x recommendations. Microvascular angina ("X" syndrome). Why does this syndrome occur?

NOVEMBER DECEMBER 2009

JSC "TATMEDIA" KAZAN STATE MEDICAL UNIVERSITY

UDC 616.12-008.331+616.379-008.64]-056.57

CARDIAC SYNDROME X: PATHOGENESIS, DIAGNOSIS, TREATMENT

Olga Polikarpovna Alekseeva, Igor V. Dolbin

Department of Internal Diseases (Head - Prof. O.P. Alekseeva) of the Medical Faculty of the Institute of the Federal Security Service of the Russian Federation, Nizhny Novgorod, e-mail: AL_OP@ mail.ru

There are many hypotheses explaining the pathogenesis of angina pectoris in cardiac syndrome X, each of which determines the leading link in the development of the disease, but cannot fully explain it. In the pathogenesis of cardiac syndrome X, such mechanisms as an increased role of the sympathetic nervous system, insulin resistance, endothelial dysfunction, similar to the mechanisms of development of metabolic syndrome X, have been identified.

Key words: metabolic syndrome, cardiac syndrome X.

Ischemic heart disease (CHD) with unchanged or little changed coronary vessels of the first and second order according to angiographic examination is called "cardiac syndrome X (CSC)". The appearance of this term, which has received great popularity in the literature, is motivated by the goal of distinguishing it from the widespread metabolic syndrome (MS) described by Keauen in 1988. Non-invasive methods for diagnosing this pathological condition have been little developed. The currently accepted criteria for CSC are described: angina pectoris, positive exercise stress test; angiographically unchanged or slightly changed coronary arteries in the absence of signs of spasm of the main epicardial

© 49. "Kazan honey. well.", No. 6.

arteries. Such combinations occur in 10-30% of patients with angina pectoris, perhaps more often, since selective coronary angiography is not performed in all cases.

The main mechanisms of the pathogenesis of cardiac syndrome X

There are many hypotheses explaining the pathogenesis of angina pectoris in CSC, each of which determines the leading link in the development of the disease, but cannot fully explain it. The most numerous supporters believe that the development of myocardial ischemia is due to a decrease in the coronary vasodilation reserve due to pathological changes developing at the level of the prearteriolar arteries. Another mechanism of blood flow disturbance in small coronary vessels, according to many researchers, is endothelial dysfunction (DE). The latter in patients with CSC entails generalized disorders in the function of smooth muscle structures of many organs and systems, which is confirmed in patients with CSC by the presence of similar disorders in other organs and systems. Insulin resistance is closely related to DE - a violation of the biological action of insulin both on the receptor,

and at post-receptor levels with compensatory hyperinsulinemia, which leads to disruption of all types of metabolism. Against the background of hyperinsulinemia, the production of vasoconstrictor substances by the endothelium, in particular endothelin-1, thromboxane A2, increases, the synthesis of nitric oxide and prostacyclin, which have vasodilating effects, decreases. The phenomena of endothelial dysfunction, in particular the production of endothelin, are disturbed during menopause, which explains the fact of the rather frequent development of CSC in women precisely in the period of loss of fertility. An increase in the activity of the sympathetic-adrenal system, the development of insulin resistance, endothelial dysfunction and impaired blood flow at the level of the microcirculatory bed with the development of inflammatory changes, transport disorders are links of the same chain that underlie the pathophysiology of angina pectoris with unchanged coronary arteries

I and 2 orders. Based on a different idea of ​​the development of CSC, myocardial ischemia is a consequence of a violation of the activity of the nervous system, in particular, the sympathetic-adrenal department at the level of both receptors and central analyzers.

According to a review of the literature on the mechanisms for the development of COAG, in most cases, priority is given to MS. What is the scenario for the development of processes in classical MS and CSC? Why do fatal complications of the cardiovascular system develop rapidly in the first case, while in the second case, patients may have a poor quality of life, but live long? How to effectively help both? We will try to answer these and other questions in this discussion. Its materials are based on our personal experience in managing patients of this category during the last

Features of clinical manifestations and instrumental diagnosis of cardiac syndrome X

We observed 148 patients with CSC who underwent a thorough examination after coronary angiography, which showed the absence of

cov stenosis of the coronary arteries. When diagnosing CSC, the features of the clinical picture, ECG, ECHOCG, the results of a bicycle ergometric test and laboratory indicators of lipid and carbohydrate homeostasis were taken into account.

The clinical features of CSC are, in comparison with typical manifestations of anginal attacks, the duration of an angina attack for more than 15 minutes and the relative ineffectiveness of nitroglycerin for its relief. In addition, we drew attention to the frequent combination of an angina attack with dysfunction of the central nervous system and gastrointestinal tract, with clinical manifestations in the form of headaches, dry mouth, heartburn, abdominal pain, stool instability with a predominance of obstipation syndrome. An in-depth study using modern instrumental methods (esophagogastroduodenoscopy, daily pH-metry of the esophagus, irrigoscopy, colonoscopy with biopsy, bulbar biomicroscopy) revealed that microcirculation disorders occupy a central place in the pathogenesis of CNS, colon, esophagus and stomach dysfunctions. It should be noted that the facts noted by us are consistent with the literature data, which emphasize the fundamental role of microcirculation, which provides hemodynamic and metabolic homeostasis. The theory of histohematological barriers is closely intertwined with the doctrine of microcirculation, the main functional element of which is the microcirculatory bed.

One of the histohematic barriers is the hematosalivary barrier (HSB), which acts as the first echelon of protection for maintaining blood constancy, the assessment of which is easily accessible by monitoring the quantitative and qualitative composition of saliva.

We have obtained interesting data on the functioning of HSB in patients with CSC. The clinical manifestations of CSC include dry mouth and significant disturbances in the rate of salivation (reducing it by 2.5 times compared with that in healthy individuals). Violations of the microcirculation

esophageal malformations in CSC patients were diagnosed by changes in the esophageal mucosa in the form of edema, erythema, and erosions in 17% of CSC patients. Clinically, the symptoms corresponded to the signs of non-erosive reflux disease (NERD), the functional class of angina pectoris in patients with CSC was higher - III and IV; All patients had a history of AMI. Microcirculation disorders in the gastrointestinal tract were manifested by irritable bowel syndrome (IBS was diagnosed in accordance with the Rome II criteria) and were confirmed by the results of histological examination of sigmoid colon biopsy specimens in 38% of individuals in the form of perivascular edema, the presence of erythrodiapedesis, and destruction of the vessels of the microvasculature. In 63.8% of patients with CSC, microcirculation disorders were detected according to the data of conjunctival biomicroscopy, which clinically corresponded to the signs of the CNS functional disorders syndrome.

A distinctive feature of CSC patients during stress echocardiography was the ascertainment of local contractility disorders and isolated diastolic dysfunction of the heart, which was detected 2.5-3 times more often in patients with CSC. Myocardial ischemia in them was also quite pronounced, but had a diffuse character. Microcirculation disorders were confirmed by coronary angiography data. In 76% of patients with CSC, a long delay of the contrast agent (more than 7-8 systoles) was recorded when viewing the coronary film, which reflected a violation of coronary blood flow at the level of intramyocardial microcirculation. The same features can explain the presence of mainly small-focal myocardial infarctions in history in patients with little-changed coronary vessels.

The study of carbohydrate homeostasis (oral glucose tolerance test, intravenous test with insulin, study of myocardial glucose consumption during the atrial pacing test during coronary angiography) confirmed the presence of insulin resistance in patients with CSC, even to a more pronounced degree than in patients with angina pectoris

with significant atherosclerotic stenosis of the coronary arteries. However, when studying lipid homeostasis (VLDL, LDL, HDL, atherogenic index), atherogenic dyslipidemias were detected only in patients with atherosclerosis of the coronary arteries. In patients with CSC, the lipid profile did not significantly differ from that in healthy individuals. Therefore, we tried to answer the following questions: why is there no decompensation of metabolic changes in patients with CSC? Why do atherosclerotic changes in coronary vessels not progress? What organs and systems are involved in the compensation of metabolic shifts?

The role of the digestive system in compensating for metabolic shifts in patients with cardiac syndrome X

What organs and systems are involved in the compensation of metabolic changes in patients with CSC? It would be logical to assume that this role is played by the system that is most adapted in the process of phylogenesis, more resistant to various influences, the protective mechanisms of which have reached a high degree of perfection in the process of evolution. This is only the digestive system. The biochemical laboratory of the body, its "metabolic boiler" is rightfully considered primarily the liver and other organs of the gastrointestinal tract, which constantly produce enzymes and hormones to regulate digestion. The latter allowed a number of researchers to isolate the gastroduodeno-hepatopancreatic zone into a separate organ, functioning as a whole. The organs of the gastrointestinal tract cannot be functionally divided among themselves - this is a digestive conveyor. Its first echelon is the salivary glands - an early adequate mechanism for a quick response. The salivary glands are the morphological substrate of the well-known functional system - GSB, which is actively involved in maintaining homeostasis.

Such indicators of the functioning of the salivary apparatus, as the rate of salivation and the biochemical composition of the blood, inevitably depend on the state of the microcirculation (MC). With the help of biochemical

indicators of salivation can indirectly assess the state of functioning of the MC at the general body level and at the level of the MC of the coronary and intramyocardial bed in patients with coronary artery disease. The significance of using the functional parameters of the salivary glands is determined not by their digestive characteristics, but by the intensity of blood flow during functional load (about 800 ml / min / 100 g of tissue). According to the latter indicator, the salivary gland is superior to the brain, myocardium, kidneys, which cannot be explained within narrow limits only by the digestive function of the salivary glands. The rate of salivation during the day ranges from 0.05 ml/min during sleep to 1 ml/min or more when salivation is stimulated (the average amount of saliva secreted by the salivary glands per day in adults is 1500 ml and can increase with stimulation of salivation up to 10 -12 liters per day). The volume of saliva is completely determined by the activity of secretory gl cells. parotis because its duct system does not reabsorb or secrete water into saliva. The complex biochemical composition of saliva, qualitatively not inferior to blood, also testifies in favor of the existence of a non-digestive function of the salivary apparatus.

What is the participation of the gastrointestinal tract in the compensation of lipid metabolism? From our point of view, there are protective factors in relation to the development of a functional blockade of transport and receptor absorption of fatty acids by cells. First of all, these include the functioning of the digestive system - at all stages, starting with a nutritional deficiency of essential polyunsaturated fatty acids and an excess of saturated ones, the function of the stomach and duodenum, lipase insufficiency of the pancreas (inability to "process" the required amount of poly-FA), disorders of the abdominal and parietal digestion in the small intestine, dysbiotic breakdowns, pathology of bile formation and bile excretion, and, finally, changes in the activity of the liver - the most important "laboratory" for the processing of exogenous and endogenous lipids, the synthesis of lipoproteins and triglycerides. 772

The liver is one of the main organs providing lipid homeostasis. 85% of cholesterol is synthesized in the liver. Synthesis of VLDL, HDL with further esterification and secretion into the blood and bile also occurs in the liver. If the functionality of the liver is sufficiently large, then lipid homeostasis disorders develop relatively slowly, which we observed in patients with CSC.

In addition, we studied the spectrum of blood and saliva fatty acids both in patients with CSC and in patients with atherosclerosis of the heart vessels (ACC). In patients with ASS, both in the blood and in saliva, a higher content of saturated fatty acids and a low content of polyunsaturated eicosaenoic fatty acids were revealed.

The role of the pancreas in maintaining lipid homeostasis is discussed in less detail in the literature. The development of acute and chronic pancreatitis in lipid disorders (primarily triglyceride metabolism) that occurs in parallel with the development of exocrine pancreatic insufficiency (EPI) is well known.

We studied the exocrine function of the pancreas using a highly sensitive and specific test with pancreatic elastase in patients with CSC, ACC, to establish its dependence on the severity of coronary atherosclerosis, assessed according to selective coronary angiography. As a result, it was possible to confirm the fact that pancreatic dysfunction occurs much more often in patients with ASS than in patients with CSC. The degree of EPI was closely related to coronary atherosclerosis. In severe EPI, in 91% of patients with ASS, the area of ​​vascular lesions of the coronary arteries exceeded 50%. EPI was not detected in 86% of patients with CSC, and only in 14% of patients it was of a moderate degree. In patients with EPI, there were pronounced changes in the fatty acid spectrum of blood and saliva towards the accumulation of saturated fatty acids and a significant decrease in the content of polyunsaturated fatty acids. At the same time, in the group of persons with ACC, the deficit

unsaturated and polyunsaturated fatty acids was more pronounced.

The role and place of pancreatic enzymes, primarily lipase, in the correction of lipid disorders remains to be elucidated. The literature reports experimental data obtained in Japan on the successful use of pancreatic elastase for the correction of severe lipid disorders in experimental animals.

A decrease in pancreatic lipase activity may be associated with bacterial overgrowth syndrome in the small intestine. So, according to G.F. Korotko et al., with EPI and a decrease in the efficiency of hydrolysis of nutrients in the small intestine, the processes of evacuation of food contents are disrupted, which, in turn, is the cause of the development of dislocation of the intestinal microflora (dysbiosis). Drugs containing pancreatic enzymes, such as Creon (minicapsulated drug), being released in the initial section of the duodenum, act on chemosensors, correct both secretory and motor functions of the gastroduodenal-pancreatic complex.

The role of the intestinal microflora in the regulation of lipid metabolism is extremely multifaceted. The role of bifidobacteria, which inhibit the activity of GMC-co-reductase, intestinal streptococci, which enhance the catabolism of cholesterol into bile acids, is discussed. Bacterial toxins, which are a key mediator of Helycobacter pylori (HP) and induce the production of proinflammatory cytokines, acute phase proteins leading to the progression of the inflammatory process, are being studied with TNF-a. Microbial tissue compliance ensures the transport of cholesterol through the intestinal wall and other functions of the gastrointestinal tract.

Thus, the correction of metabolic disorders, including lipid homeostasis, is a multilevel process. Violations that develop in any of its links can be compensated for by the adequate functioning of other links. KSH - unique

syndrome, a model of coronary heart disease with little-changed coronary vessels, on the example of which it was demonstrated that in the presence of all risk factors (insulin resistance, endothelial dysfunction, microcirculatory disorders), atherosclerosis progresses very slowly, patients live long, but "poor", their quality of life significantly reduced. Our data allow us to state that, along with other mechanisms, the organs of the gastrointestinal tract (liver, pancreas, intestines) take part in the compensation of disturbed metabolic shifts.

Treatment of patients with cardiac syndrome X

In general, the effectiveness of therapeutic measures in patients of this category is, according to various authors, only 30-50%. Drugs that cause selective blockade of angiotensin II receptors are pathogenetically justified in the treatment of CSC. We have been successfully using ACE-I and ARA II in the treatment of such patients for more than 11 years. At the beginning of the journey, we used captopril, enalapril, losartan, later we tested benazapril and candesartan.

The most demonstrative criteria for the effectiveness of treatment in the main groups were a decrease in the degree of the functional class of angina pectoris in most patients, a reduction in the number of angina attacks by 2-2.5 times a day, cardialgia became less severe. The effectiveness of nitroglycerin increased, the daily number of sublingual tablets taken decreased. Most of the patients switched to monotherapy, and among the patients who remained on polytherapy, a significant part began to take only two drugs, on average, the tolerance to physical activity controlled according to the bicycle ergometric test (VEP) doubled. The difference in the number of angina attacks, the effectiveness of nitroglycerin, the increase in exercise tolerance before and after treatment was statistically significant (p<0,05).

The effectiveness of treatment with ACE inhibitors (enalapril and benazepril) and ARA II (losartan and candesartan) in patients with CSC was 83-88% and 87-86%, respectively. Enalapril and benazepril, losartan and candesartan were well tolerated and improved the main parameters of patients' quality of life. In the comparison groups in patients with ACC after treatment with traditional antianginal therapy, a completely different situation developed, the effectiveness of drugs with monotherapy varied from 20 to 25%, with multicomponent therapy - only in some cases from 35 to 40%.

It is necessary to emphasize the important role of angiotensin II receptor blockers, especially candesartan as a selective blocker of type 1 AN receptors. We associated the special effectiveness of candesartan with the versatility of its therapeutic action, primarily with the improvement of pancreatic function. P-cells of the human pancreas have RAS, which is represented, among other things, by type 1 A11 receptors. An increase in the content of angiotensin II in the body disrupts the first phase of insulin release by P-cells, possibly due to impaired blood flow within the islets of Langerhans. Activation of the RAS in the pancreas (especially in the islet apparatus) may represent an independent mechanism of progressive damage to P-cells in diabetes mellitus. Against the background of prolonged hyperglycemia, the toxic effect of glucose and its metabolic products can activate the local RAS of the pancreas. Other factors that can stimulate the pancreatic RAS include hyperlipidemia, obesity, inflammation, and increased blood pressure. Activation of the RAS is accompanied by a violation of the structure of the islet apparatus, the development of fibrosis and apoptosis. The use of the angiotensin II receptor blocker candesartan reduces the severity of structural and functional disorders of the islet apparatus, which, in turn, is accompanied by an improvement in the function of the islet apparatus, which is assessed by the level of insulin secretion of the first phase. In addition, activation of RAS privo-774

leads to the development of oxidative stress. The tissue of the islet apparatus of the pancreas is especially sensitive to oxidative damage, since it has little endogenous antioxidant activity. The use of the AN receptor blocker candesartan cilexetil inhibits the activity of the enzyme NADPH oxidase, which increases oxidative stress, and stimulates type 1 AN receptors.

In the treatment of patients in this category, along with the correction of endothelial dysfunction (ACE inhibitors, ARA-P), insulin resistance (sulfonylurea derivatives, biguanides, thiazolidinediones, α-glusidase inhibitors), sufficient attention should be paid to maintaining the function of the gastrointestinal tract with proton pump inhibitors. , hepatoprotectors, replacement therapy with pancreatic enzymes, pre- and eubiotics. Further studies in patients with cardiac syndrome X as a model of CAD without progression of atherosclerosis may be promising in terms of studying the mechanisms of compensation for atherosclerotic changes and further searching for ways to correct them.

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Received on 12/16/08.

CARDIAC SYNDROME X: PATHOGENESIS, DIAGNOSIS, TREATMENT

O.P. Alekseeva, I.V. Dolbin

Presented was a set of hypotheses to explain the pathogenesis of angina in cardiac syndrome X, each of which defines a leading element in the development of the disease, but can not explain it completely. In the pathogenesis of cardiac syndrome X, several mechanisms were underline, such as enhancing the role of sympathetic nervous system, insulin resistance, dysfunction of endothelium, similar to the mechanisms of development of metabolic syndrome X. Clinical forms are diverse, often they are combined between themselves, forming a mosaic of clinical manifestations.

Key words: metabolic syndrome, cardiac syndrome X.

There is an exception to every rule. Its classic manifestation in cardiac pathology is syndrome X (X).

The mystery of syndrome X is that there are typical angina attacks, but the large vessels of the heart are normal.

Meanwhile, the rule is both the occurrence at the time of a painful attack of specific changes in the electrocardiogram, and the defeat of atherosclerosis of large arteries of the heart. Ischemia, as a result of insufficient blood supply to the heart muscle, is a scientifically proven fact.

Americans didn't bother with the name

How did such a strange term – Syndrome X – come about? It was first voiced by the American researcher N. Kemp, who back in 1973 decided to loudly discuss the article by R. Arbogast and M. Bourass, devoted to a comparative analysis of two groups of patients with coronary heart disease, one of them was designated as group C, and the other - group X .

The cardinal difference between patients of group X was the absence of atherosclerotic changes in large cardiac arteries during diagnostic examination (coronary angiography). However, they had typical angina attacks and electrocardiographic signs of myocardial ischemia during exercise tests. (Cannon R.O., Cattau E.L, Yarshe P.N. et al. Coronary flow reserve, esophageal motility and chest pain in patients with angiographically normal coronary arteries // Amer. J. Med. - 1990. - No. 88. - P. 217).

In order not to waste precious time searching for a new term, the Americans settled on Syndrome X.

Got to the women

Syndrome X, aka “microvascular angina”, aka “coronary syndrome X”, aka “angina pectoris with small vessel disease”, aka “small vessel disease” is a type of coronary heart disease with typical angina attacks , unchanged large coronary (feeding the heart) arteries and multiple changes in the small vessels of the heart.

About 10–20% of people with acute or chronic ischemia who undergo a diagnostic examination of the heart vessels (coronary angiography) have clean heart arteries.

Moreover, the mysterious exception does not affect men of working age at all. Oddly enough, it is mostly the lot of women 40-50 years old.

Looking for answers to the question "why?" the theories of scientists focused on:

• at a reduced level of estrogen in women,
• potential thyroid problems
• and even gender differences with men in how blood vessels are located in one and the other, and how elastic they are (Sharaf B.L., Pepine C.J., Kerensky R.A. et al. Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation Study Angiographic Core Laboratory // Am. J. Cardiol. - 2001. - Vol. 87. - P. 937-941).

Causes of pain

There is no definite answer why syndrome X develops today. It is believed that it is based on a defect in the expansion of small arteries located between the cells of the heart muscle. Normally, at the time of physical exertion, the heart's need for oxygen increases sharply, and all its vessels naturally expand.

In syndrome X, for some unclear reason, small arteries lose their ability to expand, which, with an increased level of physical activity, provokes the occurrence of angina pectoris.

Symptoms of Mysterious X Syndrome

What to pay attention to?

• In less than 50% of individuals, pain will be typical squeezing and pressing in the middle of the chest, it will occur as a reaction to physical activity, weather changes (cold, wind), acute negative emotions, they will be given to the left hand, jaw, forearm, etc.

What in these pains should alert? Long duration and lack of effect from nitroglycerin. Most of the pain is accompanied by a deterioration in well-being.

• Most have an atypical pain syndrome, reminiscent of vegetative-vascular dystonia: pains are different in nature (stabbing, cutting, shooting, aching), accompanied by lack of air, weakness, certainly emotionally colored.

And such a pain syndrome develops in suspicious persons, with a high level of anxiety and depression.

Prognosis for persons with syndrome X

The prognosis for persons with syndrome X is generally favorable for life and work. Complications (in particular, myocardial infarction, sudden death) are extremely rare. Although there are always exceptions to the rule. They are installed by a doctor who evaluates the condition of the heart and its arteries.

The risk of syndrome X lies in the more frequent development of coronary heart disease in the next 10 years in 50% of individuals with this pathology and, perhaps, in more than 2-fold increase in the risk of cardiovascular events (including myocardial infarction, stroke, congestive heart failure, death from cardiovascular diseases) - in the next five years

(Bugiardini, R. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms./ R. Bugiardini, O. Manfrini, C. Pizzi et al. // Circulation. - 2004. - Vol.-N.109.-P. 2518-2523).

Attacks of pain in syndrome X can significantly impair quality of life. It is important to remember here that approaches to the treatment of the disease will differ from those recommended for angina pectoris.

The emphasis is, firstly, on expanding the small arteries of the heart and improving the nutrition of their vascular wall, as well as on daily cardio training, changing nutrition and bringing positive emotions to life.

If a person cannot master the first without medical help, then everything else depends only on him.

Main photo: ahajournals.org

According to domestic and foreign literature, 10–30% of patients admitted to therapeutic hospitals with complaints of angina pectoris pain in the heart are diagnosed with intact coronary arteries during coronary angiography. Cardiac syndrome X (CSX) is one of the manifestations of non-coronary myocardial ischemia. The mechanism of occurrence of transient myocardial ischemia and cardiac pain syndrome in the absence of coronary artery atherosclerosis has not been fully studied. Endothelial dysfunction and myocardial microvasculature disorders are of great importance in the development of CSC. The susceptibility of symptoms in patients with CSC to medical treatment varies widely, and trials of different drug combinations are required to achieve satisfactory symptom control. However, in most cases, the proposed treatment regimens are not always effective.

angina pectoris

cardiac syndrome X

anti-ischemic therapy

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Traditionally, myocardial ischemia is understood as a pathological condition characterized by absolute or relative impairment of myocardial blood supply due to damage to the coronary arteries (CA). In most cases, myocardial ischemia is accompanied by pain or discomfort in the chest, especially during exercise. However, according to the data of domestic and foreign literature, in 10-30% of patients (approximately 50% of women and 20% of men) admitted to therapeutic hospitals with complaints of pain in the heart of an angina pectoris and positive results of stress tests, intact CAs are diagnosed during coronary angiography. . Despite the absence of a hemodynamically significant atherosclerotic lesion of the coronary artery, pain in the heart can be very intense and significantly impair not only the quality of life, but also the ability to work of patients.

Numerous clinical and experimental studies have shown that the development of ischemic syndrome and myocardial damage is possible in a number of pathological conditions and diseases, in addition to coronary heart disease (CHD). In our opinion, one of the most interesting and not fully understood manifestations of noncoronary myocardial ischemia is cardiac syndrome X (CSX). Some experts include in cardiac syndrome X patients with systemic arterial hypertension, hypertrophic or dilated cardiomyopathy. However, many of them believe that in patients with muscle bridges, arterial hypertension, valvular heart disease, left ventricular hypertrophy and diabetes mellitus, CCX should be excluded, since in these cases it is assumed that the reasons for the onset of angina pectoris are known.

There is no generally accepted universal definition of COAG, which in turn leads to terminological confusion. To designate this condition, Russian and foreign terms are used: cardialgic (cardiac) syndrome X, small vessel disease, angina pectoris with damage to small vessels, microvascular disease, Jorlin-Lykoff syndrome, etc. The term "syndrome X" was first proposed in 1973. American researcher N. Kemp in a comment to the article by R. Arbogast and M. Bourass, who conducted a comparative analysis of two groups of patients with coronary artery disease, one of which was designated as group X, characterized by the presence of an angina pectoris clinic with electrocardiographic signs of myocardial ischemia when performing stress tests with the simultaneous absence atherosclerotic changes in the CA according to coronary angiography. The definition of "cardiac syndrome X" can be considered the most common. It indicates the main clinical syndrome of the disease - pain in the left half of the chest, and also reflects the complexity of understanding the etiology and pathogenetic mechanisms of this pathology. Lanza et al. proposed to rename CSC to "stable primary dysfunction of the coronary microvessels". This proposal was made on the basis that disturbances in the coronary microcirculation are a likely cause of CSC and angina pectoris, as demonstrated in a number of studies. In this connection, a number of authors prefer the term microvascular angina pectoris (MVS), which refers to angina pectoris caused by functional and organic failure of the distal coronary bed in angiographically intact and non-spasmodic large (epicardial) coronary arteries. Despite this, current medical literature uses both the terms cardiac syndrome X and microvascular angina.

Most researchers attribute CSC to one of the clinical forms of IHD, since the concept of "myocardial ischemia" includes all cases of imbalance in oxygen supply and myocardial demand for it, regardless of the causes that cause it. However, a clear place of this form of angina pectoris among other forms of coronary artery disease has not been finally determined. There are two points of view on this matter. Some cardiologists consider MVS as a special form of coronary heart disease with failure of the myocardial microvasculature, others consider this form of angina pectoris not a type of coronary artery disease, but an independent disease of unknown etiology, manifested by angina pectoris in normal large coronary arteries. As a result, most authors consider MVS to be a form of chronic angina pectoris and, according to ICD-10, refer to code 120.8 "Other forms of angina". In this case, the diagnosis is recommended to be formulated depending on the functional class of angina pectoris, for example, “CHD with unchanged coronary arteries. Angina FC II. (Microvascular angina)".

The study of the mechanisms of pathogenesis of cardiac syndrome X has been the subject of numerous studies over the past decades. Despite this, many important questions remain unanswered. Among them are the following:

1) whether chest pains are of cardiac origin;

2) whether the pain is caused by myocardial ischemia;

3) whether other mechanisms (besides ischemia) are involved in the origin of pain, etc. .

In recent years, various mechanisms of the formation of coronary artery disease have been intensively studied. At the cellular and molecular level, the state of endothelial cells, their metabolism, the role of the receptor apparatus, etc. are assessed. Various interactions between pain threshold and microvascular dysfunction may explain the heterogeneity of CSC pathogenesis. Both pain threshold and microvascular dysfunction have gradations in severity and are modulated by various factors such as endothelial dysfunction, inflammation, autonomic neural influences, and psychological mechanisms.

Among these causes, endothelial dysfunction in CSC seems to be the most important and multifactorial; associated with major risk factors such as smoking, obesity, hypercholesterolemia, and inflammation. For example, a high plasma level of C-reactive protein, a marker of inflammation and damage, correlates with disease activity and the severity of endothelial dysfunction. Endothelial dysfunction is the earliest link in the development of atherosclerosis, it is determined already in the period preceding the formation of an atherosclerotic plaque, before the clinical manifestations of the disease, and endothelial damage, causing an imbalance in the synthesis of vasoconstrictor and vasorelaxant substances, leads to thrombosis, adhesion of leukocytes and proliferation of smooth muscle cells in arterial wall.

Another very important pathogenetic point is the decrease in the threshold of pain perception in most patients with CSC; such patients are more sensitive to nociceptive stimuli. It is noted that even small ischemia can lead to a bright clinic of angina pectoris. A key role in the pathogenesis of the disease can also be played by impaired adenosine metabolism. When this substance accumulates in excess, it can cause ischemic ST shift and hypersensitivity to painful stimuli. This is supported by a positive effect on aminophylline therapy. In general, the pathogenesis of cardiac syndrome X has not been definitively established. Summarizing the above, it can be noted that the main, most studied factors that determine the development of retrosternal pain in this pathology are defective endothelin-dependent vasodilation and a decrease in the pain perception threshold. According to other scientists, cardiac syndrome X is a combination of several risk factors for cardiovascular disease.

In the clinical diagnosis of CSC, it must be taken into account that this pathology is more common in patients aged 30-45 years, as a rule, without risk factors for atherosclerosis and with normal left ventricular function (GNOC, 2008), as well as in women compared to men. However, Rosen et al. CSC was often detected in the premenopausal period, and according to V.P. Lupanova and Yu.V. Dotsenko, postmenopausal women predominate (approximately 70%) among patients with CSC. The clinical picture of CSC is varied. In addition to typical angina symptoms, atypical symptoms of myocardial ischemia are often encountered. Pain syndrome in patients without coronary artery stenosis 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 not be stopped by taking nitroglycerin;

2) pain may have typical characteristics of an anginal attack in terms of localization, duration, but at the same time occur at rest (atypical angina pectoris due to vasospasm);

3) the manifestation of pain syndrome with typical characteristics of an anginal attack is possible, 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 MVS.

Despite the absence of a universal definition of MVS, the presence of a triad of signs corresponds to the main manifestations of the disease:

1) typical exercise-induced angina (in combination or in the absence of rest angina and dyspnea);

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 CA (stenosis< 50 %) . Также к признакам кардиального синдрома Х относят и исключенный спазм эпикардиальных венечных артерий и отсутствие известных системных заболеваний или заболеваний сердца, которые могли бы вызывать микроваскулярную дисфункцию коронарного русла .

However, a number of researchers have shown that only less than half of patients with MVS have a characteristic clinical picture of Heberden's angina, which occurs during physical or emotional stress and fully corresponds to the diagnostic criteria for stable exertional angina. Most patients with MVS have atypical pain in the region of the heart, which differs significantly from classical exertional angina. Clinical features of MVS are: frequent atypical localization of pain; the duration of pain is more than 30 minutes even after the end of physical activity; feeling of significantly pronounced prolonged pain at rest; the absence in many patients of a clear positive reaction to taking nitroglycerin; higher exercise tolerance compared with patients with stenosing atherosclerosis of the coronary arteries; more frequent association of pain with emotional rather than physical stress. Attention should be paid to pronounced changes in the emotional status of patients. Depression, fear, depression, panic attacks, irritability are very often noted; these changes significantly impair the quality of life of patients, contribute to a decrease in the pain threshold and the protracted nature of pain in the region of the heart.

The possibilities of the angiography method in assessing the state of the coronary bed, in particular the microvascular one, are limited. Therefore, the concept of "angiographically unchanged coronary arteries" is very conditional and only indicates the absence of atherosclerotic plaques narrowing the lumen of the vessels in the epicardial coronary arteries. The anatomical features of the small coronary arteries remain "angiographically invisible".

The principles of treatment of patients suffering from CSC are not fully developed. This is due to the fact that the results of clinical trials 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 the effectiveness of MVS treatment. All researchers are unanimous in their opinion that the optimal level of risk factors should be achieved in all patients with MVS. General advice on lifestyle changes and risk factor management, especially aggressive lipid-lowering statin therapy (reducing total cholesterol to 4.5 mmol/l, LDL cholesterol to less than 1.8 mmol/l), should be considered as vital components in any chosen treatment strategies.

The choice of drug therapy is often difficult for both physicians and patients themselves. The success of treatment usually depends on the identification of the pathological mechanism of the disease and is ultimately determined by the participation of the patient himself. An integrated approach to the treatment of patients with CSC is often needed. Various approaches to drug treatment are used. The recommendations of the European Society of Cardiology (2013) suggest a regimen for the medical treatment of CSC, presented in the table.

Treatment of patients with microvascular angina pectoris

Antianginal drugs are needed in patients with documented myocardial ischemia or with impaired myocardial perfusion. It is known that the effect of nitrates on the frequency of angina attacks and their duration in such patients can be unpredictable, although they bring relief to many. Sublingual nitrates are effective in 50% of patients with cardiac syndrome X. Traditional antianginal drugs are prescribed at the first stages of treatment. In connection with the dominant symptomatology of angina pectoris, therapy with β-blockers seems rational, the positive effect of which on the elimination of angina symptoms has been proven in several studies; they are the drugs of first choice, especially in patients with obvious signs of increased adrenergic activity (high pulse rate at rest or during exercise). β-blockers, in particular atenolol, reduce the number and severity of angina attacks, improve the functional status of patients with CSC. But this group of drugs is not effective in all patients with CSC - the effectiveness of this group of drugs in relieving angina symptoms is shown in two-thirds of patients with cardiac syndrome X.

Calcium antagonists and long-acting nitrates have shown mixed results in clinical trials, and their efficacy is evident when added to β-blockers in cases of persistent angina. Calcium antagonists may be recommended as first-line drugs in case of variability in the threshold for angina pectoris. Lanza et al. compared amlodipine, atenolol and nitrates in a randomized controlled trial and showed that atenolol was most effective in treating patients with cardiac syndrome X. ACE inhibitors (or angiotensin II blockers) can improve microvascular function by neutralizing the vasoconstrictor effect of angiotensin II. An improvement in exercise tolerance in patients with MVS has been demonstrated during nicorandil therapy.

Patients with persistent angina 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. The new antianginal drug ranolazine also demonstrated efficacy in patients with MVS (Table 1). A recent pilot randomized trial in patients with CSC demonstrated its effectiveness in treating angina pectoris. Finally, in the case of refractory angina, additional interventions (eg, transcutaneous neurostimulation) should be discussed.

In addition to the drugs recommended by the ESC (2013) for use in patients with CSC, there are data on the effectiveness of other drugs. Thus, the improvement of clinical symptoms in CSC was achieved by correcting endothelial function during statin therapy and estrogen replacement therapy. In controlled studies, it has been shown that in patients with angina, trimetazidine statistically significantly reduces the frequency of angina attacks, increases the time to the onset of ischemia in response to physical activity, leads to a significant decrease in the need for nitroglycerin, and improves the contractile function of the left ventricle in patients with ischemic dysfunction. Data on the effectiveness of this group of drugs in patients with CSC are not available. Palloshi A. et al showed that the use of L-arginine, a precursor of nitric oxide, for 4 weeks led to an improvement in endothelial function and relief of angina symptoms in patients with CSC. However, caution should be exercised as L-arginine worsened outcomes in post-myocardial infarction patients in a clinical study. Studies have shown that imipramine, an antidepressant with analgesic properties, and aminophylline, an adenosine receptor antagonist, improve symptoms in patients with cardiac syndrome X. Despite the efficacy of these drugs shown in studies, the evidence base is sufficient to include these drugs in the treatment regimens of patients with CSC , Not yet.

Thus, the responsiveness of symptoms to drug treatment varies widely in patients with CSC, and trials of different drug combinations are required to achieve satisfactory symptom control. However, in most cases, the proposed treatment regimens are not always effective.

Researchers' views on the prognosis of patients with cardiac syndrome X also differ significantly. According to the CASS registry study (1986), in patients with normal coronary angiograms and an ejection fraction of at least 50%, the 7-year survival rate is 96%, and with an ejection fraction of less than 50%, it decreases to 92%. In general, the long-term survival of patients with microvascular angina is better compared with obstructive coronary artery disease and may even not differ from the general population. On the other hand, the national clinical guidelines for the diagnosis and treatment of stable angina (2008) indicate that cardiac syndrome X is dangerous in its consequences to the same extent as stable angina. A number of authors have shown that in cardiac syndrome X the risk of sudden cardiac death is 2.4%. Quite rarely, in patients with syndrome X, blockade of the left leg of the His bundle occurs, followed by the development of dilated cardiomyopathy. 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. The results of a 20-year follow-up of 17435 patients in Denmark with normal coronary arteries and non-obstructive diffuse coronary artery disease with angina pectoris showed a 52% and 85% increase in the risk of major cardiovascular events (cardiovascular death, hospitalization for MI, heart failure, stroke) and 29 and 52% increased risk of all-cause mortality, respectively, in these groups, with no significant differences by gender. It has also been shown that the prognosis of patients with cardiac syndrome X deteriorates sharply when they develop atherosclerosis of large coronary arteries.

Thus, cardiac syndrome X is currently a poorly understood condition, and it is not well known to practitioners. It should be assumed that in patients with clinical and electrocardiographic manifestations of coronary artery disease, cardiac syndrome X is often not detected due to the fact that not all patients with clinical ischemic heart disease undergo coronary angiography. The mechanism of occurrence of transient myocardial ischemia and cardiac pain syndrome in the absence of coronary artery atherosclerosis has not been fully understood, just as the optimal methods of pharmacotherapy for cardiac syndrome X have not been developed.

Kozlova LK, Doctor of Medical Sciences, Professor of the Department of Faculty Therapy and Endocrinology, Orenburg State Medical University, Orenburg;

Mezhebovsky V.R., Doctor of Medical Sciences, Professor, Head of the Department of Phthisiology and Pulmonology, Orenburg State Medical University, Orenburg.

The work was received by the editors on March 6, 2015.

Bibliographic link

Cardiac syndrome X (CSX) is a pathological condition characterized by the presence of signs of myocardial ischemia (typical attacks of angina pectoris and ST segment depression ≥ 1.5 mm lasting more than 1 minute, established during 48-hour ECG monitoring) against the background of the absence of atherosclerosis of the coronary arteries and spasm epicardial coronary arteries on coronary angiography. The risk of developing this pathological condition is higher in women, especially in the postmenopausal period. In addition, the frequency of cardiac syndrome may be higher when patients with psychological problems and violations of the pain threshold are included.

Survival of patients with CSC is good, but lifestyle can significantly worsen the course of the disease. Recently, however, some studies have questioned the benignity of CSC. Poor prognostic signs can be endothelial dysfunction, which is a sign of loss of acetylcholine-induced coronary vasodilation in patients with pain, and reversible myocardial perfusion disorders on emission computed tomography with normal coronary angiography. More than 50% of patients with endothelial dysfunction developed coronary heart disease (CHD) over the next 10 years, confirmed by angiography. In other studies using the acetylcholine test, it has also been shown that in patients with endothelial dysfunction of the coronary vessels, the frequency of cerebrovascular events is higher than in patients who had normal values. The WISE study showed that women with persistent chest pain from coronary disease without coronary artery obstruction had a more than 2-fold increased risk of cardiovascular events (including acute myocardial infarction, stroke, congestive heart failure, death from cardiovascular disease). ) during 5.2 years of follow-up compared to the pain-free group.

The diagnosis of CSC is complicated by the fact that there are no sufficiently reliable, widely available and atraumatic methods to detect this pathological condition and endothelial dysfunction. Diagnostic arteriography may only be useful in ruling out CAD.

The treatment of CSC should be based on the pathogenesis of this disease, since a large choice in the physician's arsenal often leads to insufficiently effective therapy. Standard therapy with drugs used to eliminate ischemia, such as nitrates, calcium channel blockers (CCBs),
β-blockers and potassium channel activators have been used with varying success, so other approaches are required for treatment.

Pathophysiology of CSC

CSC is a heterogeneous syndrome and covers various pathogenic mechanisms (Scheme 1). First of all, most patients experience angina associated with transient myocardial ischemia, and endothelial dysfunction is one of the factors contributing to its development. It is assumed that endothelial dysfunction is primarily associated with increased formation of highly active peroxidation products (free radicals). It can also be caused by such predisposing factors as arterial hypertension, hypercholesterolemia, diabetes mellitus (DM), smoking, etc. Cardiac vasospasm can also be one of the causes of CSC and be one of the components of the triad along with Raynaud's phenomenon and migraine. It has not yet been established whether the pathogenesis of CSC in vasospasm differs from that in endothelial dysfunction. There is also a hypothesis that both mechanisms, to one degree or another, can be simultaneously responsible for the development of pathology.

Data on hereditary predisposition and violation at the molecular and cellular level do not exist today.

There is evidence to confirm that CSC is more common in people with a gene encoding the expression of receptors for gamma-interferon and kinin (B1 and B2) in peripheral blood mononuclear cells. These changes can lead to dysregulation of microcirculation and, in turn, to the appearance of a CSC clinic.

Myocardial dysfunction and ischemia

The vascular endothelium consists of a single layer of cells lining the inner surface of blood vessels and delimiting the circulating blood from other layers of the cell wall. The endothelium, in addition to the barrier function, plays a role in maintaining homeostasis and is able to produce vasoactive substances that affect vascular tone in response to various physical and chemical stimuli. Thus, nitric oxide is one of the factors produced by endothelial cells and causing vasodilation. Nitric oxide, interacting with various regulatory factors, inhibits inflammatory reactions, cell proliferation and thrombosis.

Endothelial dysfunction is characterized by the inability of arteries and arterioles to fully dilate in response to adequate stimulation, a decrease in the bioavailability of endogenous nitric oxide, and an increase in the level of endothelin-1 in blood plasma. The bioavailability of nitric oxide may be associated primarily with the development of myocardial ischemia, while the increase in the level of endothelin-1 occurs as a result of oxidative stress and an increase in the level of the endogenous nitric oxide inhibitor (serum dimethylarginine). However, it should be noted that the use of dietary supplements with antioxidant action, although it improved endothelial function, did not reduce the incidence of cardiovascular events.

Recently, Galiuto et al. in their study showed that coronary blood flow reserve was significantly reduced in a subgroup of patients with CSC who, when tested with adenosine, experienced pain and ST segment depression on the ECG. In another study by Lanza et al. also noted a significant decrease in the reserve of coronary blood flow in patients with CSC and symptoms of reversible perfusion disorders on nuclear magnetic resonance examination compared with patients who did not have signs of transient ischemia. In the same study, results were obtained confirming that capillary dysfunction as a result of endothelial disorders may be responsible for myocardial ischemia in CSC.

It must be remembered that many patients with CSC suffer from transient chest pain that occurs during exercise and is associated with transient myocardial ischemia, which in turn can be detected using both conventional ECG and more modern methods of research (nuclear magnetic resonance and etc.) .

Some studies have found that CSC may be accompanied by metabolic disturbances. For example, Buffon et al. found that CSC can significantly increase the production of cardiac hydroperoxides with oxidative properties in the coronary sinus after atrial stimulation. In addition, an increase in the levels of hydroperoxides and conjugated dienes has been found, similar to patients with total coronary artery occlusion as a result of balloon expansion during percutaneous coronary intervention.

Inflammatory response and COSC

Endothelial dysfunction may also be associated with systemic inflammatory reactions and, accordingly, an increase in the level of C-reactive protein (CRP). Some studies have shown that CSC may be accompanied by an increase in CRP levels when possible infectious and inflammatory diseases are excluded, compared with control patients without CSC. It was also found that there is a significant correlation between a high level of PSA and the frequency of ischemic episodes during Holter monitoring and with the magnitude of ST segment depression during exercise tests in patients with pain and normal angiography. There is also a small number of studies supporting the effectiveness of non-steroidal anti-inflammatory drugs and steroid hormones in the treatment of CSC. In addition, the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and statins in the treatment of CSC may be associated with their anti-inflammatory action.

Insulin resistance and CSC

Insulin resistance is more common in patients with CSC than other laboratory criteria. When comparing the main group (patients with CSC) and the control group, hyperinsulinemia and elevated CRP levels in the glucose tolerance test were significantly more common in the representatives of the first group. In addition, patients with CSC had higher fasting insulin levels. In a study by Botker et al. showed that impaired insulin resistance in CSC patients is due to a defect in glucose transport across the cell membrane. Moreover, insulin resistance may be associated with decreased activity of endothelium-dependent vasorelaxation. Since insulin is a key component in the mechanism of proliferation of smooth muscle cells and the occurrence of vasoconstriction, it can also be observed in CSC.

In some studies, it was also found that in DM, a large number of advanced glycosylation end products are formed, which affect the elastic properties of the vascular wall, increasing its rigidity, and according to the results of recent studies in CSC, there is an increase in arterial wall stiffness and the thickness of the carotid intima-media index. .

Effect of estrogen

As noted earlier, CSC is more common in women than in men. Moreover, this pathology is recorded more often in the period of pre- and postmenopause, as it is assumed, this is due to estrogen deficiency. Some studies confirm that the use of replacement therapy has been obtained positive results in women with CSC: the intensity and frequency of pain associated with exercise decreased.

Clinic and diagnostics of COSC

Among patients with CSC, middle-aged people predominate, mostly women. The main complaint is episodes of chest pain of an angina pectoris character, arising during physical exertion or provoked by cold, emotional stress; with typical irradiation, in some cases the pain is longer than with coronary artery disease, and is not always stopped by taking nitroglycerin (in most patients, the drug worsens the condition).

During instrumental examination, in a significant part of patients, incoming or persistent conduction disturbances are found (by the type of blockade of the left leg of the His bundle). ECG at rest during an attack of retrosternal pain, exercise tests and 48-hour Holter monitoring revealed signs of ischemic depression of the ST segment, exceeding 1.5 mm in amplitude and 1 minute in time. The diurnal profile of ischemic episodes shows their high frequency in the morning and afternoon hours; at night and in the early morning ischemia is rare (as in patients with coronary artery disease). Myocardial stress scintigraphy with 201 Tl shows typical ischemic focal disorders of drug accumulation.

Laboratory during an attack reveals the accumulation of myocardial lactate. When conducting a dipyridamole test in patients, there is no increase in coronary blood flow at the level of small coronary vessels, clinically this is manifested by an increase in the severity of ischemia, the appearance of pain in the chest. The ergometrine test is positive, and when assessing cardiac output, its decrease is noted against the background of the drug administration.

Today, the following are distinguished as diagnostic criteria:
typical chest pain and significant ST segment depression during exercise (including treadmill and bicycle ergometer);
transient ischemic ST segment depression ≥ 1.5 mm (0.15 mV) lasting more than 1 minute with 48-hour ECG monitoring;
positive dipyridamole test;
a positive ergometrine (ergotavine) test, a decrease in cardiac output against its background;
absence of atherosclerosis of the coronary arteries in coronary angiography;
increased lactate during ischemia in the analysis of blood from the area of ​​the coronary sinus;
ischemic disorders during stress myocardial scintigraphy with 201 Tl.

Differential Diagnosis. At the first treatment of a patient with cardialgia, the question always arises of the differential diagnosis of this condition. At this stage, it is important to correctly ask the patient, find out the features of the pain syndrome and analyze, first of all, how they correspond to the typical manifestations of angina pectoris.

When collecting an anamnesis, it is worth paying attention to the age and gender of the patient, the presence of risk factors and occupational hazards. Significant assistance can be provided by the available medical documentation indicating comorbidity (heart disease, long-term anemia, thyrotoxicosis, chronic lung disease, etc.), which can simulate the clinic of angina pectoris. An objective examination reveals signs characteristic of diseases that mimic angina pectoris: an increase in the thyroid gland, pain on palpation of the thoracic spine, intercostal spaces, shoulder joint, changes in respiratory sounds, tachycardia, arrhythmia, noises in the heart area. Even if, on the basis of a conversation with a patient, a study of medical records and an objective study, you are convinced that cardialgia is not associated with IHD or CSC, but with some other reason, you should not neglect additional examinations that can refute your data.

The plan for additional examination of the patient should include:
complete blood count (exclusion of anemia, inflammatory changes that may be associated with a latent infection, signs of activity of a rheumatological disease);
lipid spectrum (determining the likelihood of atherosclerosis);
fasting glucose level and / or, if necessary, a glucose tolerance test (excluding diabetes as a risk factor for developing coronary artery disease);
acute phase indicators (SRP, sialic acids, seromucoid, fibrinogen), rheumatoid factor - to exclude rheumatological pathology;
studies to rule out syphilis;
standard ECG and/or exercise tests, Holter monitoring;
chest x-ray (heart size, lung fields), which allows you to exclude the presence of pneumonia, tuberculous process in the lungs, pleural overlays;
if there are signs indicating the possibility of detecting osteochondrosis or other pathology of the spine, x-ray of the thoracic and cervical spine in frontal and lateral projections, functional tests;
echocardiography - in the presence of heart murmurs, changes in the size of the heart during topographic percussion or according to radiography;
fibrogastroduodenoscopy - in the presence of complaints from the digestive system and at the same time burning pain behind the sternum (to exclude gastroesophageal reflux disease);
ultrasound examination of the abdominal organs - to exclude radiating pain caused by cholecystitis, pancreatitis, etc.;
coronary angiography - performed in patients in whom atherosclerotic lesions of the coronary arteries cannot be completely excluded.

The listed studies in most cases allow us to more accurately differentiate the diseases included in the "syndrome of pain in the left half of the chest"; at the same time, studies can be carried out according to the algorithm of optimal diagnostic feasibility. In other words, based on the data of subjective and objective methods of examination, it is necessary to draw up a plan for further research (taking into account economic costs and reduction in diagnostic time).

As a guide, you can use the algorithm presented in Scheme 2. The task of diagnostic search in this case is the separation of cardiac and extracardiac causes of pain; ECG (routine, exercise tests or Holter monitoring) was chosen as the starting method for conducting diagnostics, which is available in most medical institutions and is easy to use and cheap. The detection of any changes on the ECG in more than 90-95% of cases is alarming in terms of the cardiac genesis of the pain syndrome (although it is worth remembering the possibility of a combination of cardiac and extracardiac causes), and their absence convinces the opposite. Next, it is necessary to divide patients by age and gender, and then analyze the most likely cardialgia in a particular age and sex group and methods for verifying the diagnosis. The epidemiological approach, taking into account age and gender factors, significantly reduces the cost and speeds up the procedure for additional research.

To clarify the extracardiac cause of pain, it is necessary to search for an additional syndrome, which is carried out on the basis of patient complaints, anamnesis, and minimal physical examination. After clarifying the syndrome (pathology of the digestive, respiratory, musculoskeletal systems, etc.), the range of diagnostic search will narrow even more.

Thus, in the differential diagnosis of cardialgia, the main methods should be a conversation with the patient, physical examination, ECG (routine and monitoring and / or exercise), the identification of leading syndromes using the principle of optimal diagnostic feasibility. Epidemiological factors (sex, age, smoking) matter.

Current therapeutic strategies

Beta blockers

β-blockers may be considered as first-line agents for the treatment of patients with CSC, especially in patients with symptoms or with increased sympathetic activity, confirmed by elevated BP, in response to exercise. In a small, randomized, double-blind, placebo-controlled study in response to a 7-day course of propanolol, there was a significant reduction in ischemic manifestations and recovery of the segment with constant ECG monitoring, while in the subgroup where verapamil was prescribed, no positive dynamics was observed. Also, in another small study, atenolol reduced the incidence of angina episodes, reversible ST segment depression in response to exercise, and improved left ventricular performance on Doppler echocardiography in patients with CSC. Also, the only method that had a positive effect on the clinical course of CSC was the appointment of atenolol in comparison with amlodipine and nitrates. Several recent studies have shown positive results in the treatment of patients with CSC with the appointment of nevibolol (selective β 1 -blocker). So, studies noted the restoration of reserve coronary blood flow, increased release of nitric oxide from the vascular endothelium.

The positive effect of this group of drugs is associated with a decrease in heart rate, myocardial oxygen consumption, anti-ischemic effects and a decrease in the increased adrenergic tone characteristic of patients with CSC.

However, it should be noted that different studies provide different statistics on the effectiveness of β-blockers and is 19-60%.

Nitrates

Today, the issue of the effectiveness of nitrates in patients with CSC is debatable. Thus, in early studies it was shown that the use of sublingual nitrates relieves pain in only 42% of patients with normal coronary angiography. Bugiardini et al. demonstrated a positive effect of intracoronary and sublingual nitrates in their study. Radice et al. also showed improvement in exercise test scores and ST segment recovery, but these scores were significantly worse than in patients with CAD. There are also studies that suggest that exercise test scores may worsen in CSC patients with sublingual nitroglycerin.

Thus, given the lack of results of large randomized controlled trials on the use of nitrates in patients with CSC, today it is impossible to speak about their effectiveness in patients with chest pain and normal coronary angiography.

Calcium channel blockers

Data on the use of CCBs in patients with CSC are also conflicting.

In a small, randomized, double-blind, controlled trial, treatment with CCBs (nifedipine and verapamil) significantly improved angina pain control and improved exercise performance. In another uncontrolled study, Montorsi et al. showed that sublingual use of nifedipine for four weeks reduced ST segment depression during exercise, improved coronary blood flow indicators according to angiography. The same results were obtained with the use of dihydropyridine in patients with CSC.

However, diltiazem has not shown beneficial effects in patients with CSC. The same results were obtained in a randomized, double-blind, placebo-controlled study using verapamil.

Nicorandil

Potassium channel activator - nicorandil - has arterial dilating properties. In experimental studies, the antihypoxic effect of this drug on isolated cardiac muscle was shown. Further studies demonstrated anti-ischemic and cardioprotective effects. Yamabe et al. showed restoration of myocardial blood supply with intravenous administration of nicorandil to patients with myocardial ischemia and normal coronary angiography. In another randomized, double-blind, placebo-controlled study, two weeks of nicorandil treatment in patients with CSC resulted in resolution of ischemic events, ST-segment recovery, and improvement in exercise testing compared with placebo.

Thus, nicorandil is a promising direction for studying and administering therapy in patients with CSC.

Hormone Replacement Therapy

Estrogen replacement therapy may have a beneficial effect in the treatment of CSC in pre- and postmenopausal women. However, its use may be limited by an increased risk of blood clots and breast cancer. In addition, there is evidence that efficacy in the initial stages of treatment decreases with long-term therapy.

Promising directions in the treatment of CSC

Given the new data on the pathophysiology of CSC, namely the role of endothelial dysfunction and oxidative stress, the main therapeutic approaches are currently being revised. Particularly promising is the study of the effect of ACE inhibitors and statins. Biguanides and xanthine oxidase inhibitors may also have anti-ischemic effects and may potentially be useful in patients with CSC. In addition, there is active development on the use of ivabradine and trimetazidine in patients with stable angina pectoris, but their use in patients with CSC requires further study.

ACE inhibitors

According to the results of a large number of studies, ACE inhibitors improve endothelial dysfunction and may have a positive effect in CSC. Thus, in a randomized, blind, placebo-controlled study, X. Kaski et al. showed a decrease in ST segment depression, an improvement in performance during an exercise test in patients with CSC and reduced coronary blood flow. These results were confirmed by another small double-blind trial using cilazopril. In a double placebo-controlled study by Chen et al. also demonstrated that enalapril use for eight weeks not only significantly improved exercise test scores, but also coronary blood flow reserve and endothelial nitric oxide levels in patients with CSC.

The positive effects of the use of ACE inhibitors in CSC are associated with the restoration of the level of endothelial nitric oxide and a reduction in the ratio of l-arginine and dimethylarginine (an index of systemic metabolism of nitric oxide).

Statins

The drugs of the statin group, in addition to the lipid-lowering effect, also have a number of other actions. One of them is anti-inflammatory activity and, as a result, a positive effect on vascular endothelial function.

In a randomized, blind, placebo-controlled study, Kayikcioglu et al. showed the efficacy of pravastatin 40 mg in patients with CSC. At the same time, there was an improvement in performance during the exercise test and endothelial function (assessed by the current at the level of the brachial artery). The same results were obtained in a similar study by Fabian et al. when using simvastatin at a dose of 20 mg for 12 weeks when comparing patients with CSC randomized to the main group and placebo. In a recent randomized, prospective, blinded, placebo-controlled study, the combination of atorvastatin (40 mg/day) and ramipril (10 mg/day) for six months in patients with CSC significantly improved quality of life with normalization of exercise test scores and results of the Seattle Patient Questionnaire. with angina.

In addition, there was a significant improvement in vascular endothelial function and a decrease in antioxidant activity in the vascular wall. Thus, the combination of an ACE inhibitor and a statin could be a significant advance in the treatment of patients with CSC.

Metformin

Metformin has angioprotective properties and may improve vascular endothelial function. In a small study by Jadhav et al. in women with chest pain and normal coronary blood flow on nondiabetic angiography, metformin 500 mg twice daily for eight weeks improved capillary endothelial function on combined Doppler and iontophoresis and reduction of myocardial ischemia, according to the test of monotonous physical labor and ST segment depression, the Duke scale and the level of chest pain.

Allopurinol

Allopurinol is a potent xanthine oxidase inhibitor that has been widely used in the prevention and treatment of gout since 1966. It has also been investigated for its ability to inhibit the oxidation
6-mercaptopurine and antitumor activity. Recently, its angioprotective properties have been discovered, regardless of the severity of uric acid reduction and xanthyl oxidase inhibition. In experimental and clinical studies, the properties of allopurinol and its active metabolite oxypurinol have been shown to improve blood perfusion in the ischemic myocardium, reduce the severity of symptoms and manifestations of chronic heart failure and inflammatory changes. In addition, allopurinol may decrease myocardial oxygen demand.

The significance of oxidative stress in the pathogenesis of CSC is also confirmed by the data of recent studies, in which the level of activity of peroxidation products directly correlates with the risk of developing cardiovascular events. Although therapeutic strategies aimed at reducing the activity of peroxide products in patients with CSC have shown their limited effectiveness. The combined use of ACE inhibitors and statins affects both the processes of peroxidation and vascular endothelial function, which provides good treatment results. Allopurinol at high doses (600 mg/day) improves endothelial function and reduces oxidative stress in patients with chronic heart failure, independent of the effect on uric acid metabolism. At the same time, endothelial function improved by an average of 143%, which is much more effective than other therapeutic strategies. The efficacy of allopurinol in CSC will be evaluated in the current APEX trial (http://clinicaltrials.gov/ct2/show/NCT00512057).

Other promising areas

Non-pharmacological treatment of patients with CSC should only be considered as an adjunct to medical treatment. Thus, in a small study, for eight weeks, patients with CSC performed tests with physical activity for endurance, while the time to perform physical activity before the onset of pain increased.

In some studies, it has been proven that targeted psychological programs to change lifestyle and behavior have a positive effect on pain reduction, exercise tolerance.

The antidepressant imipramine has analgesic properties due to visceral effects. Small doses of imipramine reduced the severity of pain in patients with normal coronary angiography, but did not affect the quality of life of patients.

Intravenous bolus administration of l-arginine reduces the level of endothelin-1 and restores the activity of nitric oxide, which in turn leads to the normalization of endothelial function.

Conclusion

CSC is a pathological condition resulting from various etiological factors with a pathogenesis not always explained. Although early studies showed a benign course of CSC, it has now been proven that more than 50% of patients with CSC develop organic disorders at the level of the coronary vessels, confirmed by angiography, over the next 10 years. However, the use of modern effective therapeutic strategies aimed at reducing oxidative stress and restoring endothelial function can significantly improve the quality of life and prognosis in patients with CSC.

The bibliography is under revision.

The review was prepared by V. Savchenko.

One of the most common types of metabolic disorders is the metabolic syndrome. This condition is directly related to urbanization, malnutrition and low physical activity. Other names for the disease: death quartet, syndrome X.

For the first time about the metabolic syndrome began to talk in the eighties of the last century. Doctors summarized data on the prevalence of obesity, diabetes, hypertension, atherosclerosis. It turned out that often patients rarely have one of the listed diseases. Usually pathologies are combined and aggravate each other.

The prevalence of metabolic syndrome is quite high. In developed countries, people over 30 years of age show signs of this pathology in 10–35% of cases. In the elderly, the components of the syndrome occur in 35–45% of cases. It is believed that men are less likely to experience such violations. Metabolic syndrome in women often forms at menopause and is associated with a drop in estrogen levels.

In recent decades, metabolic syndrome has been rapidly spreading among young people. Thus, the number of patients among adolescents has almost doubled over the years. Now the components of the syndrome are found in every 15 minors.

Disease criteria

Scientists are still discussing the criteria for syndrome X. It is usually considered that a patient has pathology if at least 2 of the listed signs are observed.

Possible symptoms of metabolic syndrome:

• insulin resistance against the background of impaired carbohydrate tolerance;
• dyslipidemia (increased triglyceride levels, decreased concentration of high density lipoproteins);
• increased blood clotting (tendency to thrombosis);
• hypertension due to high tone of the sympathetic nervous system;
• abdominal obesity (according to criteria for men and women);
• hyperuricemia.

Low tissue sensitivity to insulin is confirmed by blood tests. The laboratory examines the level of endogenous insulin, blood glucose. Next, the ratio of these indicators is calculated. Caro and Homa indices are calculated using special formulas. In addition, patients are given an oral glucose load test (sugar curve).

Insulin resistance and low carbohydrate tolerance confirm:

• fasting sugar more than 5.5 mmol/l;
• insulin above normal (reference values ​​2.7–10.4 mcU/ml or 6–24 mcU/m);
• the value of the Caro index is less than 0.33;
• the value of the Homa index is greater than 2.7;
• glycemia 2 hours after exercise more than 7.8 mmol/l.

Dyslipidemia is a violation of the concentration of fats in the blood. Usually, patients observe an increase in the level of atherogenic cholesterol fractions against the background of a decrease in high-density lipoproteins. The criteria for men and women are slightly different.

Metabolic syndrome is accompanied by:

• an increase in blood triglycerides up to 1.7 mmol/l and above;
• an increase in low-density lipoproteins up to 3.0 mM/l or more;
• a decrease in high-density lipoprotein less than 1.0 mM/l in men (1.2 mM/l in women).

Hemostasis is assessed by the criteria of clotting rate, bleeding time, etc. The metabolic syndrome is characterized by hypercoagulability and an increase in the concentration of a plasminogen activator inhibitor.

Hypertension is detected by repeated pressure measurements and 24-hour monitoring.

Arterial hypertension is diagnosed at a pressure greater than 140/90 mm Hg. Even an increase to 135/80 mm Hg. Art. already meets the criteria for syndrome X.

The tone of the sympathetic nervous system can be assessed using special tests and instrumental measurements. In practice, a simple dermographism test is used for screening.

Abdominal obesity is diagnosed according to anthropometric data. The patient's waist and hips are measured. Then the ratio between these indicators is calculated. Metabolic syndrome results in an increase in the waist/hip ratio greater than 0.95 in men and greater than 0.86 in women. As a criterion, they simply use the waist size. Abdominal obesity is diagnosed with a value of more than 96 cm in men and 88 cm in women.

Protein metabolism is assessed by the level of uric acid in the blood. In men, its level can exceed 416 μM / l, and in women - 387 μM / l. Many patients experience clinical manifestations of gout.

Causes of pathology

Scientists explain the symptoms of metabolic syndrome as insulin resistance. It is the low sensitivity of tissues to the hormone of pancreatic beta cells that is considered the trigger for other metabolic disorders.

The defect in insulin receptors is inherited. If parents have this pathology, then the probability of its transmission to children is 50-70%.

Insulin resistance is manifested in the absence of a sufficient response of tissues to the hormone. Cells do not perceive signals due to the small number of receptors or their low efficiency. As a result, insulin in physiological concentrations has no effect. This leads to an increase in blood sugar, an energy deficit within the cells, dehydration, etc. To overcome insulin resistance, the pancreas begins to secrete more of the hormone. When its blood level exceeds the upper limit of normal, adverse effects begin to develop.

Too much insulin causes:

• activation of the sympathetic nervous system;
• increased blood pressure;
• damage to the vascular wall;
• development of polycystic ovaries and hyperandrogenism in women;
• development of erectile dysfunction in men.

Insulin resistance of the liver tissue has a particularly adverse effect on metabolism. Hepatocytes synthesize an excess of atherogenic cholesterol and triglycerides. Also, due to changes in the liver, hyperglycemia develops (gluconeogenesis is activated).

In patients with the main features of the metabolic syndrome (hypertension, obesity, dyslipidemia, hyperuricemia and hyperglycemia), insulin resistance is found in 95-100% of cases. This confirms the leading role of low sensitivity to the hormone in the development of other components.

Prevention of metabolic disorders

It is impossible to eliminate the genetic cause of metabolic pathology. But it is possible to act on risk factors for the development of the disease.

Increased insulin resistance leads to:

• sedentary lifestyle;
• excess body weight;
• excessive caloric content of food;
• chronic stress;
• smoking.

For the prevention of metabolic syndrome, men and women are recommended the right lifestyle:

• rejection of bad habits;
• balanced diet;
• dosed physical activity.

It is especially important to maintain body weight within the normal range. Body mass index is used to detect obesity. This parameter is calculated using a special formula. Normally, the index does not exceed 25 kg / m 2.

If a patient is diagnosed with obesity, then he needs to count calories in the diet, limit fatty and sweet, regular exercise.

Sometimes getting rid of extra pounds is very difficult. If lifestyle modification does not give visible results, then obesity is treated with drugs or surgery.

Syndrome X treatment

All components of the metabolic syndrome require constant medical monitoring. Patients should be observed by specialists and regularly tested.

Medical treatment for metabolic syndrome includes:

• statins and fibrates;
• antihypertensive drugs;
• antiplatelet agents and anticoagulants;
• hypoglycemic drugs;
• allopurinol and similar agents;
• orlistat, sibutramine, etc.

Metabolic syndrome requires treatment by doctors of different specialties: therapist, endocrinologist, cardiologist, gynecologist or andrologist, gastroenterologist.

The syndrome has a common root cause - insulin resistance. For pathogenetic treatment, drugs are used that eliminate this defect.

Physicians use:

• biguanides;
• incretins;
• thiazolindiones;
• alpha-glucosidase inhibitors.

Metformin biguanide is usually the drug of choice in men and women. Its influence on the body is realized at the level of the liver, adipose and muscle tissue.

Metformin:

• reduces the production of glucose by hepatocytes;
• inhibits the absorption of glucose in the intestine;
• corrects dyslipidemia;
• reduces the severity of hypertension;
• Reduces the tendency to thrombosis;
• increases the number of insulin receptors;
• reduces the concentration of endogenous insulin;
• promotes weight loss.

Metformin does not cause hypoglycemic conditions, since it does not activate insulin synthesis in beta cells.

Incretins may also be prescribed. These modern drugs have been used for more than 10 years to combat insulin resistance and hyperglycemia. They act on the cells of the pancreas. Incretins improve insulin synthesis. They also normalize the production of glucagon. This hormone ceases to be released into the blood during hyperglycemia, which means that insulin resistance is overcome. Incretins also affect the liver. As a result, the sensitivity of hepatocytes to insulin increases.