[Albuminuria as a marker of atherosclerosis burden and a possible predictor of adverse events in patients with polyvascular disease].

BACKGROUND: The role of albuminuria as a marker of the atherosclerosis burden and a predictor of prognosis in patients with polyvascular disease (PD) has been little studied. AIM: To evaluate the prevalence, association with atherosclerosis burden, and prognostic value of albuminuria in relation to cardiovascular and bleeding complications in patients with PD. MATERIALS AND METHODS: The data was obtained from the prospective registry REGATA-1 (NCT04347200). Seventy four patients (75.7% males, median age 67 [61-69] years) with PD (CAD and peripheral arterial disease) were enrolled. All patients received aspirin and rivaroxaban 2.5 mg. The albumin-creatinine ratio in a single morning urine sample, estimated glomerular filtration rate (eGFR), and von Willebrand factor levels were determined. RESULTS: Mild albuminuria (10-29 mg/g) was detected in 45.9% of patients, moderate and severe (≥30 mg/g) - in 29.7%; eGFR<60 ml/min - in 21.7%, chronic kidney disease (CKD) according to the full KDIGO criteria (eGFR and/or albuminuria ≥30 mg/g) - twice as often (39.2%). The frequency of nephroprotective therapy prescription was insufficient. The level of albuminuria did not correlate with von Willebrand factor (endothelial dysfunction marker), but was associated with affecting of 4-5 vascular beds (ROC AUC 0.775; p=0.011). During the follow-up (12 [8-18] months) 3 patients developed MACE, 11 - BARC 2-3 bleedings. Neither albuminuria nor eGFR were predictors of MACE, bleeding, or net clinical benefit. CKD (KDIGO) was also not associated with bleedings. CKD (KDIGO) was independent predictor of MACE (in significant multiple regression model beta - coefficient for CKD was 0.097; p=0.042), however, the small number of end points allows us to speak only of a hypothesis-generating trend. The implementation of CKD (KDIGO) has increased the predictive value of the REACH score. CONCLUSION: Albuminuria is highly prevalent in patients with PD. It is a marker of atherosclerosis burden. CKD, diagnosed taking into account the level of albuminuria, can be used in a comprehensive assessment of cardiovascular risk in this category of patients.

[The becoming of reactions of lipolysis in phylogenesis. The palmitic and oleic triglycerides as substrates. Insulin, condition of normolipemia and formation of hyper lipoproteinemia type IIb, IV and V].

According to phylogenetic theory of general pathology, when living in ocean all were carnivorous (piscivorous) fatty acids transferring to cells in form of non-polar triglycerides nitially began apoB-48 chylomicrons, continued lipoproteins of very low and low density and fnalized its apoB-100 endocytosis. The fatty acids are transferred by chylomicrons + lipoproteins of very low density + lipoproteins of low density and non-polar triglycerides are hydrolyzed by hepatic glycerolhydrogenase and co-enzyme apoC-III; according WHO classifcation, hyperlipoproteinemia corresponds to type V. On land, in herbivorous who are not yet synthesized insulin, apoB-48 and chylomicrons left process of non-polar triglycerides transferring. In lipoproteins of very low density and lipoproteins of low density, the carnivorous transfer exogenous palmitic non-polar triglycerides. The herbivorous also transfer palmitic non-polar triglycerides though synthesized by hepatocytes from glucose endogenically. In herbivorous, transferring of palmitic non-polar triglycerides prior to synthesis of insulin is forming apoB-100 in composition of lipoproteins of very low density and lipoproteins of low density. The hydrolysis of palmitic non-polar triglycerides in lipoproteins of very low density is activated by hepatic glycerol hydrogenase and apoC-III; cells absorb lipoproteins of low density by means of apoB-100 endocytosis. The content on lipoproteins in blood plasma under electrophoresis of lipoproteins corresponds to hepatic glycerol hydrogenase type IIb. In frst and second types of fatty acids transferring in form of triglycerides to lipoproteins of very low density + lipoproteins of low density predominate palmitic fatty acid, triglycerides of the same name and palmitic metabolism of fatty acids in vivo. The insulin initiated the third type of transferring of oleic fatty acid by now to insulin-depended cells only in oleic lipoproteins of very low density; hydrolysis of oleic triglycerides is activated by late in phylogenesis post-heparin hepatic glycerol hydrogenase and apoC-II cofactor. The dynamic apoE is actively bound by apoB-100 forming apoE/B-100 ligand. At later stages of phylogenesis insulin formed fatty acids transferring in form of oleic triglycerides in lipoproteins of very low density of the same name without forming of oleic lipoproteins of low density; the electrophoregram of lipoproteins reflects absence of hepatic glycerol hydrogenase. In phylogenesis three types of fatty acids transferring to triglycerides in composition of lipoproteins formed sequentially: 1) chylomicrons + lipoproteins of very low and density + lipoproteins of low density; 2) lipoproteins of very low density + lipoproteins of low density; 3) only in lipoproteins of very low density. The frst one is specifc to piscivorous (carnivorous) while living in ocean. The second one is implemented by herbivorous while they didn't begin to synthesize insulin and hepatocytes not yet transform all endogenous palmitic fatty acid into oleic fatty acid. Insulin initiated: a) transferring of oleic fatty acids to lipoproteins of very low density without forming oleic lipoproteins of low density; b) highly effective oleic metabolism of fatty acids in vivo: c) becoming of biological function of locomotion. The aphysiological induction by substrate, surplus of palmitic fatty acids in food initiate negative alterations in composition of lipoproteins in opposite direction than in case of phylogenesis. When homo sapiens, herbivorous in phylogenesis, begins to misuse carnivorous (meat) food then instead of normolipoproteinemia in blood plasma under electrophoresis of lipoproteins one can initially detect transitory hyperlipoproteinemia type IV and then prolonged hyperlipoproteinemia type IIb. If patient factually passes on to carnivorous diet then hyperlipoproteinemia type V is developing. If content of exogenous palmitic fatty acid in food surpasses physiological capacities of its transferring in oleic triglycerides as palmitoyl-oleyl-palmitate glycerol, palmitic triglycerides as oleyl-palmitoyl-palmitate glycerol begin to form and epigenetically aphysiological non-ligand palmitic lipoproteins of very low density → lipoproteins of low density are formed. Their circulation in blood is a cause of hypertriglyceridemia, higher level of cholesterol-lipoproteins of low density, compensatory increasing of apoC-III. Then occurs induced by substrate formation of hyperlipoproteinemia initially of type IV, then of type IIb and fnally of type V. The pathogenesis of atherosclerosis and atheromotosis is activated when homo sapiens, herbivorous in phylogenesis, begin to misuse carnivorous food affecting biological functions of trophology, reaction of exotrophy (external nutrition), function of homeostasis, endoecology and function of adaptation. The formation of palmitic metabolism if fatty acids instead of oleic one is a cause of chronic defciency of energy and ATP synthesis in vivo. Insulin activates absorption of glucose by cells with purpose to use it for synthesis of oleic fatty acids. In the frst place, insulin regulates in vivo metabolism of fatty acids and only in second place metabolism of glucose.

[How surplus of palmitic fatty acid in food initiates hypertriglyceridemia, increases cholesterol of low density lipoproteins, triggers atherosclerosis and develops atheromatosis.]

In phylogenesis, the first transfer of all fatty acids to cells is implemented by high density lipoproteins. Later, unsaturated and polyene fatty acids are transferred to cell by low density lipoproteins. The insulin-depended cells absorb palmitic saturated fatty acid, oleic mono-unsaturated fatty acid and of the same name triglycerides in very low density lipoproteins. The hepatocytes secrete palmitic, oleic and linoleic very low density lipoproteins separately. In blood, under hydrolysis of triglycerides, cells absorb ligand palmitic and oleic very low density lipoproteins by force of апоЕ/В-100 endocytosis; they are not transformed into low density lipoproteins. The palmitic saturated fatty acids in the form of polyether of cholesterol turn into linoleic very low density lipoproteins from high density lipoproteins at impact of protein transferring polyene ethers of cholesterol. They transform very low density lipoproteins into low density lipoproteins of the same name; the cells absorb them by force of апоЕ/В-100 endocytosis. In physiological sense, amount of oleic very low density lipoproteins are always more than palmitic of very low density lipoproteins. Under syndrome of insulin-resistance there is no transformation of palmitic saturated fatty acid synthesized from glucose in vivo into oleic mono-saturated fatty acid. The hepatocytes secrete into blood mainly palmitic very low density lipoproteins which amount exceeds oleic very low density lipoproteins. Under slow hydrolysis in blood, main mass of palmitic very low density lipoproteins becomes palmitic low density lipoproteins. These very lipoproteins initiate hyperlipidemia, increase content of cholesterol of cholesterol-low density lipoproteins, lower cholesterol-high density lipoproteins, decrease bio-availability of polyene fatty acids for cells, trigger development of atherosclerosis and formation of atheromatosis in intima of arteries. The aphysiologic effect of surplus of palmitic saturated fatty acid in vivo and triglycerides of the same name can't be eliminated under increasing of content of ω-3 polyene fatty acids in food and effect of statines. All this is to be rationally applied in prevention of hypertriglyceridemia, atherosclerosis, atheromatosis of coronary arteries, ischemic heart disease and myocardium infarction.

[The physical chemical and biological features of triglycerides. The cell absorption of functionally different palmitic+oleic lipoproteins of very low and density and linoleic+linolenic lipoproteins of low density.]

The earlier insulin-independent low-density lipoproteins and more late insulin-dependent very low-density lipoproteins implement different functions at the stages of phylogenesis. The disorder of biological function of trophology, alteration of fatty acids in triglycerides, prevalence of palmitic very low-density lipoproteins over oleic very low-density lipoproteins supply mitochondria of cells with non-optimal substrate - palmitic saturated fatty acid for gaining energy, ATP synthesis. Physiologically, cells implement oleic alternative of fatty acids metabolism, oxidizing mainly ω-9 endogenous oleic mono-unsaturated fatty acid. The pathology of low density lipoproteins is primary deficiency of poly-unsaturated fatty acids in cells, atherosclerosis and atheromotosis of intima of arteries of elastic type with development of dense plaques from poly-unsaturated fatty acids in the form of polyethers of cholesterol. The pathology of very low-density lipoproteins includes: a) syndrome of resistance to insulin; b) pathology of phylogenetically earlier insulin-independent visceral fatty tissue - metabolic syndrome; c) pathology of phylogenetically later insulin-dependent subcutaneous adipocytes - obesity; d) secondary atherosclerosis, under cumulation of palmitic low-density lipoproteins in blood with development of atherothrombosis of intima of arteries, soft plaques rich with triglycerides. As for the prevention of disorders of transfer of fatty acids to very low-density lipoproteins and low-density lipoproteins is common in many ways - minimization of aphysiological effect of surplus amount of food, biological function of diet. The prevention at the level of population includes: a) maximal limitation of content of palmitic saturated fatty acid in food; b) moderate increasing of polysaturated fatty acids, ω-3 poly-saturated fatty acids predominantly; c) increasing of physical activity. The pharmaceuticals are not provided by biology in primary prevention of metabolic pandemics under aphysiological impact of environment factors.

[Atheromatosis of arterial intima].

Phylogenetically late arterial intima of the elastic type contains no proteins for the transfer of ligandless oxidized low density lipoproteins (LDLP) for sedentary macrophages adsorbed on the matrix. Phylogenetically early cells realize the extracellular digestive reaction by releasing proteolytic enzymes (metalloproteinases) into intimal matrix that hydrolize matrix proteoglycans, adsorbed ligandless LDLP, detritus, and complete lysosomal hydrolysis of the most hydrophobic polyenic cholesterol esters (poly-ECS). Smooth muscle cells migrate from the middle muscular layer of the arterial wall, change their contractile phenotype to secretory one, and synthesize in situ de novomatrix proteoglycans. The arterial wall has three layers (monolayer endothelium, intimal media (smooth muscle cells), and adventitia) only in elastic type arteries. It is desirable to elucidate functional differences between phylogenetically early sedentarymacrophages and monocytes-macrophages of later origin and understand whether theydepends on specific features of activity of scavenger eceptors, CD36 translocases, expression of acid hydrolases synthesis for poly-ECS or realization of the extracellular digestion reaction. We believe that formation of atheromatous masses takes place in the matrix of arterial intima rather than in lysosomes taking into account limited possibilities for monocytes-macrophages to realize endocytosis of ligandless LDLP from the matrix. Given that atheromatosis is a syndrome of deficit of essential polyenic fatty acids (PFA) in the cells, intimal atheromatosisshould be regarded only as partial utilization of excess PFA in the matrix of elastic type arteries. At later stages of phylogenesis, intima was formed from media smooth muscle cells.

[THE LIPOLYSIS IN PHYLOGENETICALLY EARLY LIPOPROTEINS OF LOW DENSITY AND MORE LATER LIPOPROTEINS OF VERY LOW DENSITY: FUNCTION AND DIAGNOSTIC VALUE OF APOE AND APOC-III].

According to phylogenetic theory of general pathology, the function of low density lipoproteins (LDL) and hydrolysis of triglycerides (TG) in them under the effect of hepatic glycerol hydrolase apoC-III (HGH) developed at much earlier stages of phylogenesis than functioning of insulin-dependent phylogenetically late very low density lipoproteins (VLDL). For millions ofyears, lipolysis and HGH+apoC-III have activated transfer of polyenic fatty acids (FA) in the form of cholesteryl polyesters (CLE) from high density lipoproteins (HDL) to linoleic and linolenic LDL under the effect of cholesteryl ester transfer protein. It is reasonable to suggest that hepatocytes physiologically secrete oleic and palmitic VLDL and linoleic and linolenic LDL. Cells uptake ligand oleic and palmitic VLVL by apoE/B-100 receptor-mediated endocytosis. Physiologically, VLDL are not converted to LDL. If hepatocytes secrete palmitic VLDL in greater amounts than oleic VLDL upon slow hydrolysis ofpalmitic TG and under the effect of postheparinic lipoprotein lipase+apoC-II, only some proportion of palmitic TG is uptaken by cells as VLDL, and the rest is converted in ligand-free palmitic LDL These LDL increase plasma contents of TG and LDL-cholesterol and form small dense palmitic LDL. Expression of HGH+apoC-III synthesis compensates TG hydrolysis in nonphysiological palmitic LDL. In vivo, apoC-III is neither physiological no pathological inhibitor of lipolysis. Increase in plasma apoC-III content is an indicator of accumulation of non-physiological palmitic LDL and atherosclerosis-atheromatosis risk factor ApoE content ofpalmitic LDL increases together with apoC-III, i.e., apoE in ligand VLDL is not internalized via apoE/B-100 endocytosis. An increase in apoC-III and apoE contents are reliable in vivo tests for the rise inpalmitic FA, palmitic TG and excessive secretion of palmitic VLDL by hepatocytes. ApoC-III and apoE contents in LDL are additional tests to evaluate the efficiency of atherosclerosis prevention when physiological function of trophology and biological reaction of exotrophy are normalized.

[THE EFFECT OF SATINS: ACTIVATION OF LIPOLYSIS AND ABSORPTION BY INSULIN-DEPENDED CELLS LIPOPROTEINS OF VERY LOW DENSITY, INCREASING OF BIO-AVAILABILITY OF POLYENOIC FATTY ACIDS AND DECREASING OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

The Russian cardiologic R&D production complex of Minzdrav of Russia, 121552 Moscow, Russia The statins are synthetic xenobiotics alien to animal cells. They are unlikely capable to manifest pleiotropic effect. It is feasible to evaluate effect of statins by stages: a) initially a specific inhibition of synthesis of cholesterol alcohol; b) further indirect activation of hydrolysis of triglycerides in lipoproteins of very low density; c) nonspecific activation of cells' receptor absorption of palmitic and oleic lipoproteins of very low density and then d) linoleic and linolenic lipoproteins of low density with all polyenoic fatty acids. On balance, statins activate absorption ofpolyenoic fatty acids by cells. Just they manifest physiological, specific pleiotropic effect. The statins inhibit synthesis of pool of cholesterol alcohol-lipoproteins of very low density condensed between phosphatidylcholines in polar mono-layer phosphatidylcholines+cholesterol alcohol on surface oftriglycerides. The low permeability of mono-layer separates substrate-triglycerides in lipoproteins of very low density and post-heparin lipoprotein lipase in hydrophilic blood plasma. The higher is ratio cholesterol alcohol/phosphatidylcholines in mono-layer of lipoproteins of very low density the slower is lipolysis, formation of ligand lipoproteins of very low density and their absorption by cells under apoB-100-endocytosis. The statins normalize hyperlipemia by force of a) activation of absorption oflipoproteins of very low density by insulin-depended cells and b) activation of absorption of lipoproteins of low density by all cells, increasing of bio-availability of polyenoic fatty acids, activation of apoB-100-endocytosis. The limitation in food of content of palmitic saturated fatty acid and increasing of content of ω-3 polyenoic fatty acids improve "bio-availability" of polyenoic fatty acids and their absorption by cells and also decreases cholesterol alcohol/phosphatidylcholines and biological pleiotropic effect of essential polyenoic fatty acids. According our opinion, atherosclerosis is intracellular deficiency of polyenoic fatty acids. The value of cholesterol alcohol-lipoproteins of low density is equimolar to content of lipoproteins of low density in blood which under low bio-availability can't to absorb cells byforce of apoB-100-endocytosis.

[The conformation of apoB-100 in phylogenetically and functionally different lipoproteins of low and very low density: algorithm of formation of phenotypes of hyper lipoproteinimia (a lecture)].

The cells' malabsorption of three classes of lipoproteins--chylomicrons and lipoproteins of low and very low density,--form under electrophoresis six phenotypes of hyperlipoproteinemia. In phylogenesis, cells absorb lipoproteins in a consecutive way by apoE/B-48, apoB-100 and apoE/B-100 receptor endocytosis. The domain-ligand in lipoproteins of very low density is forming when apoB-100 takes active conformation "deformed bilayer apoprotein-lipid" in association with domain apoE apoE/B-100 ligand is formed. Another active conformation apoB-100 in domain is globule with lipids in "pocket" forming apoB-100 ligand In blood 9 subclasses are formed: pre-ligand and post-ligand chylomicrons, lipoproteins with low density and lipoproteins with very low density. The ligand lipoproteins bind receptors of membrane and absorb cells. Both pre-chylomicrons, pre-lipoproteins with low density, pre-lipoproteins with very low density and post-chylomicrons, post-lipoproteins with low density, post-lipoproteins with very low density remain in blood. The sub-classes of lipoproteins form at electrophoregram 6 phenotypes of hyperlipoproteinemia: phenotype I-pre-chylomicrons + pre-lipoproteins with very low density; phenotype IIa--post-lipoproteins with low density; phenotype IIb--pre-lipoproteins with very low density; phenotype III--post-chylomicrons + pre-lipoproteins with very low density; phenotype IV--pre-lipoproteins with very low density; phenotype V--pre-chylomicrons + post-chylomicrons + pre-lipoproteins with very low density + post-lipoproteins with very low density. The formation under electrophoresis of primary phenotypes and secondary types of hyperlipoproteinemia occurs according single algorithm. In aphysiological sense, the major mass of palmitic and oleic lipoproteins with very low density absorb cells without transformation into lipoproteins with low density. Only linoleic and linolenic lipoproteins with very low density which are formed after binding of apoB-100 of triglycerides the same name and which are not much in blood acquire density of lipoproteins with low density physiologically. Under high content of triglycerides in blood main mass of lipoproteins with low density consists of aphysiologic palmitic lipoproteins with very low density with hydrated density lipoproteins with low density, the cause of hyperlipoproteinemia of phenotype III is genotype e21e2 apoE; hyperlipoproteinemia of phenotype V--genotype e4/e4 and probably toxic inhibition of activity (synthesis) phylogenetically late stearil-KoA-desaturase-2.

[The palmitic and oleic modes of metabolism of fatty acids. The exogenous syndrome of resistance to insulin under disorder of biologic function of nutrition (trophology)].

The hyperglycemia and insulin are two phylogenetically different humoral regulators of metabolism in vivo. The development of hyperglycemia occurred billions years hitherto under implementation of nutrition function. The insulin was formed in the process of development of biologic function of locomotion. The syndrome of resistance to insulin consists in the derangement of humoral regulation of metabolism of fatty acids and glucose at the phylogenetically different levels in vivo both in paracrine cells cenosis and at the level of organism. The exogenous and endogenic syndromes of resistance to insulin are distinguished. The exogenous resistance to insulin is formed under physiologic function of insulin system when hormone effect is prevented by derangement of biologic function of trophology (nutrition)--the formation of such palmitinic mode of metabolism of fatty acids as substrates for oxidation in mitochondria. The endogenic syndrome of resistance to insulin consists in discrepancy of regulation of biologic functions at the level of organism under realization of locomotion function and at the level of paracrine cells cenosis under realization of biologic function of adaptation, endoecology (support of "cleanness" of intracellular medium) and its biologic reaction of inflammation, homeostasis function. The syndrome of resistance to insulin is energetic issue in vivo. Primarily, insulin regulates metabolism of fatty acids and only secondly metabolic transformations of glucose. In case ofpalmitinic mode of metabolism offatty acids in the enzymes with the same parameters are involved in biologic reactions. The palmitinic triglycerides are not optimal due to aphysiological slow biochemical and physico-chemical reactions.