Lifestyle changes to improve HDL. It has been shown that HDL levels increase with weight loss, regular aerobic exercise, reduced alcohol consumption and smoking cessation. Thus, a weight loss of 3 kg leads on average to an increase in HDL cholesterol by 1 mg / dL. And regular aerobic exercise in sedentary adults can increase HDL cholesterol by 10-20%. Nicotinic acid to increase HDL cholesterol. Nicotinic acid, a B vitamin, causes an increase in HDL cholesterol by 15–35% and a decrease in triglycerides by 20–50%. Nicotinic acid leads to an increase in specific subtypes of HDL, which contain apoproteins pre-B and AI and have a protective effect on the heart. According to the Coronary Drug Project, the use of niacin reduces the risk of non-fatal myocardial infarction even after 15 years of follow-up. The most common side effect is hot flashes, which can be reduced by gradually increasing the dose, taking the drug with meals or at night, and using aspirin or ibuprofen 30 minutes before taking nicotinic acid. The most dangerous side effect is liver damage. Fibrates to raise HDL and lower triglycerides. Fibric acid derivatives bind to nuclear receptors PPARct, which are involved in lipid and carbohydrate metabolism. They increase the activity of lipoprotein lipase, which leads to an increase in triglyceride hydrolysis and the elimination of triglyceride-saturated lipoproteins from the bloodstream, while the level of free fatty acids released from adipocytes decreases. Fibric acid derivatives are the most effective means for lowering triglycerides (by 20-55%), in addition, they also increase HDL (by 10-20%). They affect LDL levels in different ways, and sometimes even an increase in LDL is noted in the treatment of patients with hypertriglyceridemia. Fibric acid derivatives are drugs of choice for severe hypertriglyceridemia (over 1000 mg / dL). It has been shown that derivatives of fibric acid are effective both for primary prevention and for the treatment of already confirmed coronary artery disease. The VA-HIT study evaluated the efficacy of gemfibrozil versus placebo in the treatment of men with proven coronary artery disease, median LDL (less than 140 mg / dL) and low HDL (less than 40 mg / dL). After 5 years of follow-up, the use of gemfibrozil resulted in a 31% decrease in triglycerides and an increase in HDL cholesterol by 65%, while the LDL level did not change. The relative risk of non-fatal myocardial infarction and mortality from coronary heart disease decreased by 22%. However, it should be noted that, according to the FIELD study, which evaluated the efficacy of fenofibrate compared with placebo in 9795 patients with diabetes, fenofibrate did not lead to a significant decrease in these indicators. Although the authors of the study believe that the reason was the higher frequency of initial statin use in the control group, which led to an underestimation of the possible beneficial effect.
Statins to increase HDL cholesterol Statins increase HDL levels only slightly, and this effect is not associated with a decrease in LDL cholesterol. The most pronounced level of HDL increases when taking simvastatin (by 8-16%), rosuvastatin (by 8-14%) and pravastatin (2-12%), while atorvastatin, fluvastatin and lovastatin increase HDL by no more than 9% … Treatment with statins can also lead to a moderate reduction in triglyceride levels, by about 7-30%. Moreover, the more significant the decrease in LDL, the greater the decrease in triglycerides. Fish oil to increase HDL-C Fish oil contains polyunsaturated fatty acids in high concentrations and leads to a decrease in TAG levels by up to 45%, although it can also cause an increase in LDL-C. Omega-3 fatty acids are used in adults in addition to diet therapy to reduce triglycerides when they are markedly elevated (500 mg / dL). The mechanism of their action is poorly understood, but it is likely that they inhibit acyl-Coadiacylglycerol acyltransferase and increase peroxisomal oxidation in the liver. New approaches to increasing HDL cholesterol Several completely new and highly interesting therapeutic approaches are currently being developed and tested. One of them is associated with the suppression of the carrier protein cholesterol esters, a plasma glycoprotein synthesized in the liver and found in the bloodstream in connection with HDL. This protein provides the transport of cholesterol esters between various lipoproteins. Initially, its effect is atherogenic, since it promotes the transition of cholesterol esters from HDL to VLDL and LDL, that is, it reduces the concentration of HDL cholesterol and increases the concentration of LDL cholesterol. It was shown that pharmacological suppression of this protein leads to an increase in the reverse transport of cholesterol from peripheral tissues to the liver due to an increase in HDL levels and an increase in cholesterol uptake in the liver through the scavenger receptor B-1. Thus, suppression of the carrier protein during irreversible binding to a molecule called JTT-705 in 152 patients while receiving pravastatin led to an increase in HDL levels by 28%. Similarly, the use of torcetrapib, which selectively and effectively suppresses the carrier protein, against the background of low HDL concentration, led to its increase and decrease in LDL levels both with monotherapy and in combination with a statin. Other new techniques in the testing phase include direct infusions of plasma-derived or synthetic apoprotein A-1 and drugs that increase the number of scavenger receptors.
Progesterone and its synthesis. Effects of progesterone
Progesterone is synthesized in the corpus luteum. It is released in the second half of the menstrual cycle and stops a few days before the onset of menstruation. Its action follows the earliest action of estrogen. Progesterone increases vascularization and secretory activity of the endometrium, preparing it for implantation of a fertilized egg, and inhibits the mobility of the uterus. If the formation and increment of progesterone persist, menstruation stops. In the last period of pregnancy, the placenta plays an important role in the formation of progesterone. The biosynthesis of progesterone also occurs in the adrenal cortex from acetate, cholesterol, and pregnenol. This compound is very similar to deoxycorticosterone, only in the progesterone molecule the C-21 lacks an OH group. Therefore, progesterone has some effect on electrolyte metabolism. Cholesterol is the precursor to progesterone in the adrenal glands and in the corpus luteum; it is first oxidized to pregnenolone, which is then converted to progesterone. In the second half of the menstrual cycle, another steroid derivative appears in the urine of women – pregnandiol. This steroid is formed from progesterone as a result of the restoration of the keto group (C-20) and saturation of the ring A. Always after an injection of progesterone, a certain and fairly constant percentage of pregnanediol appears in the urine. Like other steroids in urine, it is paired with glucuronic acid. Pregnanediol and pregnanthriol are excreted in excess in the urine in the case of virilization resulting from adrenal hyperplasia. These compounds are degradation products of progesterone and 17-hydroxyprogesterone, secreted from the adrenal glands. When progesterone is injected into a non-pregnant woman, 10-15% of it is excreted in the urine as pregnandiol. In a pregnant woman, 25–35% of the progesterone administered is converted to pregnandiol. In pregnancy, almost all pregnanediol comes from progesterone produced by the placenta. A non-pregnant woman secretes 3-8 mg of pregnandiol per day during the period of the highest activity of the corpus luteum, and a pregnant woman, 50-175 mg. In the second month of pregnancy, the amount of pregnanediol released increases from the initial level (3-8 mg) to 50 mg per day.
In the last third of pregnancy, the trend for an even higher steroid release continues, peaking two weeks before delivery. Pregnandiol completely disappears from urine four days before delivery . The breakdown products of progesterone also appear in the urine of men. So, in the urine of men, 1 mg / day of pregnenolone was found. In the ovaries of women, from 20 to 25 mg of progesterone is formed within a month. Progesterone is in the blood plasma, bound to lipoproteins, inactivated and removed from the blood by the liver. In it, progesterone is reduced to inactive pregnandiol, combines with glucuronic acid, enters the general bloodstream and is excreted in the urine. With a malignant tumor of the testes, progesterone is formed in them in large quantities, and pregnandiol appears in the urine of a sick man. Progesterone during pregnancy stimulates the growth of the mammary glands due to the glandular structures; has an anti-ovulation effect if given to a woman from 5 to 25 days of the normal menstrual cycle; in large doses increases the retention of salts and water in the body; stimulates the formation of glycogen in the epithelium of the uterus. The content of glycogen in the endometrium is 170 mg% in the proliferative phase and reaches 1100 mg%. on the 18th day of the menstrual cycle. Progesterone functions as a hydrogen acceptor in the conversion of estrone to estriol. Thus, it participates in the biochemical process of estrogen formation. Progesterone is administered in oil solutions (doses of 1-10 mg). It is used to treat recurrent abortions and to prevent toxemia in pregnant women with diabetes who have a progesterone deficiency, and to relieve menorrhagia, metrorrhagia, dysmenorrhea, chronic mastitis, and to relieve labor pain.
Stable and unstable atherosclerotic plaques and their rupture The formation of atherosclerotic plaques in the arteries takes a very long time, for years. Sometimes the plaque becomes multi-layered. The formation of plaques proceeds in waves, when the phase of progression, the growth of the plaque is replaced by a more or less prolonged phase of stabilization, and then the phase of reverse development. The period of formation of plaques for a long time runs latently, without showing any symptoms, i.e. clinically asymptomatic. This period of the preclinical course of atherosclerosis (according to A.L. Myasnikov) usually covers children, adolescence and young people. And only when the degree of stenosis of the coronary or other arteries reaches about 50% or more, when ischemic foci periodically appear in the myocardium and other tissues that are supplied with blood by the affected artery, the disease passes into the clinical period, manifesting itself in various forms of coronary artery disease, IBI, intermittent claudication etc. Atherosclerotic plaque can also occur in vascular shunts and prostheses. Atherosclerotic plaques are heterogeneous in origin and composition. In their formation, not only lipids, macrophages, platelets, but also other blood cells, microorganisms, viruses, antibodies can take part. During the formation of an atherosclerotic plaque, lipoperoxides accumulate in the blood of patients, which have a damaging effect on many structures of the body, including cells of the vascular endothelium. In this place, the antithrombotic function of the endothelium is lost and platelets are activated with the release of growth factors, etc. The formation of an atherosclerotic plaque in humans proceeds for a long time, continuing for many years and even decades. The course of ischemic heart or brain disease is determined not only by the size of the plaque, but also by many other factors – its localization, growth rate, as well as the presence or absence of collaterals in this area, etc. The composition of atherosclerotic plaques is of great importance, since this determines their stability or instability. It is known that atherosclerotic plaques differ in many parameters – size, place of their formation, composition, etc. At a certain stage of its development, an atherosclerotic plaque can rupture. Rupture of atherosclerotic plaques is the most common cause of acute disorders of the coronary or cerebral circulation. Plaques that are prone to rupture are called unstable or prone to rupture. These atherosclerotic plaques are not necessarily large and rarely cause significant stenosis of the coronary or other arteries. But these plaques, as a rule, contain a lot of lipids and have a thin outer fibrous plate (operculum), which is usually infiltrated by inflammatory cells. Lipid composition is important in the stability of plaques: a high content of cholesterol esters helps soften atherosclerotic plaques, while crystalline cholesterol stabilizes its structure.
Plaque rupture often occurs at its apex or at the base, on the border with the intact surface of the vessel. As noted, there is not always a direct correlation between the degree of instability of plaques and their size. Often rupture of atherosclerotic plaques occurs against the background of moderate stenosis of the coronary arteries. Rupture can be facilitated by stress, physical overload, toxic, mechanical and other effects on the vessel wall. The most important consequence of the rupture of atherosclerotic plaques is the formation of a thrombus and subsequent rapid occlusion of the affected artery. Revealing and stabilizing the structure of such unstable atherosclerotic plaques is an important direction in the prevention and treatment of coronary atherosclerosis. It should be recognized that currently there are no reliable methods for detecting atherosclerotic plaques prone to rupture. It is logical to assume that the formation of unstable plaques occurs in the phase of progression of atherosclerosis, after a long period of hypercholesterolemia and dyslipidemia. Infiltration of the plaque by inflammatory cells indicates a tendency to rupture. It was found that in the place of rupture of the inner membrane or erosion of coronary arteries, thrombosed by plaque, there is an inflammatory infiltrate. The development of the inflammatory process in atherosclerotic plaques is facilitated by the presence of atherogenic lipoproteins, especially oxidized ones, microorganisms or autoantigens (for example, heat shock proteins). The penetration of activated macrophages and T-lymphocytes into the plaque, which produce cytokines and proteins that dissolve the matrix, leads to a weakening of its connective tissue base, making the plaque loose. Smooth muscle cells by producing matrix, collagen and metalloproteinases – inhibitors of enzymes that dissolve the matrix – can partially neutralize these effects. Calcification can be an important element of atherosclerotic plaques. When studying the mechanism of calcification, it was shown that this is not passive adsorption of calcium phosphate crystals by a plaque, but an active process similar to the formation of bone tissue. It is biochemically closely related to the general process of atherosclerotic plaque formation (MB Belkind, AA Lyakishev, VE Sinitsin). The study of these processes can be carried out using fluoroscopy and computed tomography. However, accurate localization and quantitative measurement of coronary calcifications became possible only with the advent of electron beam computed tomography (ELCT). Quantification of coronary calcium, according to numerous studies, can be a marker of the prevalence of atherosclerotic lesions of the coronary arteries. ELCT has proven to be a very sensitive method in the diagnosis of both obstructive and non-obstructive coronary artery disease. There was a high correlation of coronary calcifications detected by ELCT with the severity of coronary lesions according to angiography and intravascular ultrasound, the volume of atherosclerotic plaques determined histologically, the number of risk factors for coronary artery disease, the number of cardiovascular complications of atherosclerosis. It is assumed that spasm of the coronary arteries can lead to compression of the lipid mass in the center of the plaque, its rupture, followed by the entry of lipids and other substrates of the plaque into the lumen of the artery. In some cases, hypercoagulability and a decrease in the fibrinolytic activity of the blood can also become a direct cause of coronary thrombosis with the subsequent development of deep myocardial ischemia. IJ Kullo et al. highlight some properties of atherosclerotic plaques, predisposing to their rupture. I. Molecular signs of atherosclerotic plaque rupture: • secretion of matrix metalloproteinases; • increased production of tissue thromboplastin. II. Structural signs of atherosclerotic plaque rupture: • large accumulation of lipids; • thin fibrous plate; • reduced collagen content. Cellular: • the presence of chronic inflammation; • increased content of markers of inflammation; • increased content of macrophages and increased activity; • accumulation of T-lymphocytes near the site of the future rupture; • increased vascularization; • reduced content of smooth muscle cells; • increased content of mast cells and increased activity. The rupture of atherosclerotic plaques usually leads to the formation of a blood clot. Thrombosis of the coronary arteries, sharply reducing blood flow in the affected vessel, can manifest itself as unstable (progressive) angina pectoris, myocardial infarction, or sudden cardiac death, especially in the absence of sufficient collateral blood flow. If this thrombosis occurs in the cerebral arteries, it causes cerebral ischemia and often stroke. However, with a slight rupture of atherosclerotic plaques, a high blood flow rate in the affected arteries, and sufficient activity of the fibrinolytic system, the severity of thrombosis may be minimal. In such cases, the rupture of atherosclerotic plaques may be clinically limited by microsymptomatology or not manifest at all. In about 8% of patients with coronary atherosclerosis who died from noncardiac causes, small fresh ruptures of atherosclerotic plaques were found on autopsy (IJ Kullo et al.). In patients who previously suffered from diabetes mellitus or arterial hypertension, the frequency of such ruptures increases to 22%. It is logical to assume that asymptomatic ruptures of atherosclerotic plaques with subsequent asymptomatic thrombosis at the site of their rupture occur much more often in clinical practice than they are diagnosed in vivo. Such cases can lead to the development of not only complications such as unstable angina pectoris, myocardial infarction, transient cerebral ischemia, but also cause sudden cardiac or cerebral death. As for the possibility of transforming unstable plaques into stable ones, the most real possibility of such a process, naturally, is to the greatest extent associated with the normalization of lipid metabolism. Then the excess of cholesterol, triglycerides, atherogenic lipoproteins accumulated in the plaque is gradually removed from it by high density lipoproteins. Despite the fact that during treatment with cholesterol-lowering drugs, the lumen of the coronary arteries increases slightly, the observed decrease in the frequency of complications of coronary heart disease suggests that such drugs stabilize the structure of atherosclerotic plaques, turning them from unstable to stable. At the same time, it should be borne in mind that such active methods of treating coronary atherosclerosis as coronary artery bypass grafting and coronary angioplasty have absolutely no effect on the mechanism of atherosclerosis development, on its course, and therefore do not reduce the risk of possible rupture of atherosclerotic plaques at this time. nor in the future. It is important that in patients with unstable angina pectoris, in acute coronary syndrome, in patients with myocardial infarction, coronary circulation disorders often occur not in one, but in two or even three arteries at once. This instability – an exacerbation of ischemic heart disease (and sometimes ischemic brain disease) occurs due to the simultaneous multiple destabilization of atherosclerotic plaques. And the latter is based on the exacerbation of the atherosclerotic process. This entire cascade of pathogenetic changes that determine the course, the immediate and distant outcome of the disease, must be taken into account at all stages of the treatment process, especially at the earliest stages of the disease. From a practical point of view, it is very important that a certain degree of reversibility is inherent in atherosclerotic plaques at any stage of development, including with a fully formed plaque, due to its lipid components. At the same time, the degree of stenosis in this place can be reduced by an amount that, in a critical situation, in some cases determines the further course of coronary disease and its outcome. Therefore, the issue of conservative treatment of atherosclerosis should be resolved unambiguously – treatment must be carried out at any age if the above criteria are met, including after surgical interventions on the coronary arteries, and even more so in case of lipid metabolism disorder and unstable course of ischemic heart disease.