Plasmapheresis for atherosclerosis

Atherosclerosis is perhaps the most frequent and severe human disease. It is accompanied by vascular disorders, which are the main causes of lipid metabolism lead to the accumulation of low-density- and very low-density cholesterol, triglycerides while reducing the content of anti-atherogenic factors - high-density lipoprotein (HDL). All further consequences –  deposition of atherosclerotic plaques in the vessel walls with narrowing of the lumen is quite well known, as well as their main symptoms: narrowing of the coronary vessels – coronary heart disease, cerebral vascular narrowing with ischemic attacks, peripheral vasoconstriction, leading to gangrene of the extremities.
Nevertheless, in the pathogenesis of atherosclerosis a certain role plays and autoimmune factors. This primarily refers to the anticardiolipin antibodies. In addition, there are identified IgG-antibodies to vascular endothelium, cardiomyocytes, cardiac conduction system fibers and smooth muscle [Morozov B.N. et al., 2006].
It is believed that the oxidation of low density lipoprotein (LDL) may change their antigenic structure, which stimulates the appearance of autoantibodies against these structures with the formation of immune complexes containing oxidized LDL + autoantibodies. These complexesfacilitatethe accumulation ofcholesterol estersin macrophages andfibroblasts,withincreased synthesis ofcytokines, suchasIL1and TNF-a.Excitedmacrophages(monocytes) are beginning to adhereto the vascular endotheliumand moveinto the subendothelialspace, wherethe releaseof the abovecytokinesmayplay a leadingrole in the interactionof endothelial cellswithmononuclear cells, leading totheirdirect or indirectdamage, as well as proliferation of smooth musclecellsof the vascular wall[Lopes-VirellaMF, Virella G.,1994; Mironova M. et al.,1997].


Elevated levels ofapolipoprotein (a) [Lp (a)] alsopromotesmonocytechemotactic activity, forcing them tobe introducedthroughthe vascular endotheliumin thesubendotheliallayer, which is the firststep inthe atherogenicprocess[Poon M.et al.,1997].

There is possiblelink betweenatherosclerosisand immuneinflammation.Thus, "intercellular adhesion molecule", secretedby macrophages, are fixed to the vessel endothelialcellsandare attractedthereT-lymphocytes and monocytes,andthenpromotetheir migrationinto the vessel wall[Watanabe T., Fau J.,1998].
Macrophages engulf low density lipoproteins, are vacuoled ("froth") to the release of some cytokines (IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, TNF-a), acute phase of inflammation (C-reactive and “stressor" protein), which determine the formation of immune inflammation focus and the subsequent development of atherosclerotic plaque. Function of C-reactive protein (CRP) is a "recognition" as well as infectious agents and damaged cells and their decay products. Direct opsonization CRP and complement activation contribute to the restoration of tissue injury [Van de Vijver L.P.L. et al., 1996; Watanabe T. et al., 1996; Nagornev V.A., Rabinovich V.S., 1997].
Interestingfindingswere obtainedby morphological study ofthe vascular intimaafterendarterectomyoperations. In the compositionof atherosclerotic plaqueswith75% of caseswere foundChlamidia pneumoniae,in 35% – cytomegalovirusand 10% –Herpes simplexvirustype 1. These dataindicate a possibleroleof these pathogens inthe pathogenesis of atherosclerosis[Chiu B.et al.,1997]. Chlamydia pneumoniaeinfection ispossiblein the cellsof the endothelium andsmooth muscleof the vascular wall, resulting in localinflammation andfibrosiswiththe formationof the typical atheroscleroticplaque.The presence of suchinfectionsandstimulatescytokineoutputinfringingthrombus-resistiveendothelial functionandenhancingcontractilefunctionof smooth muscleof the vascular wall[Murray LJet al.,1999].

Bacterial and viral infections are also considered potential triggering factor. Infection has viscosity increased blood hypercoagulation, affected plasma lipid profile. For infections of gram negative bacteria endotoxin contribute to the formation of free radicals in the vascular endothelial cells that can oxidize the lipoproteins. Many pathogens – E. coli, Chl. pneumoniae and cytomegalovirus allocate special "termo-shock proteins", against which antibodies are formed. However, the antigenic properties of these proteins are close to human autoantibody that promotes "antigenic mimicry." When the antibodies raised against such pathogens they are as antibodies against self antigens, in particular – vascular endothelial cell antigens. Since these autoantigens remain in their place throughout life, so the signals for the formation of such autoantibodies supported indefinitely [Mayr M. et al., 1999]. These data are forced to think about the need for timely removal of such antibodies against pathogens for during or at the conclusion of infectious processes that such pathological antigenic mimicry has not had time to consolidate.


Additionally, vascular lesion sites include deposition of immunoglobulins and complement, including lytic "complex lesion membranes" S5v C9, indicating that complement activation in atherosclerosis.

Significant role in the pathogenesis of circulatory disturbances play hemo-rheology violations. Increasing the viscosity of the blood and plasma depends on improving the concentration of fibrinogen and lipid fractions – total cholesterol, LDL and triglycerides. Are significant and increasing aggregation blood cells while reducing of erythrocytes deformation ability. All together, it predisposes to poor blood flow, especially in the presence of local narrowing of blood vessels at the level of plaques also [Walzl M. et al., 1998]. In the presence of antiphospholipid antibodies, such as anti-β2-glycoprotein I, increases platelet aggregation, contributing hypercoagulable state which is especially dangerous in the presence of vasoconstrictions [Kandiah D.A. et al., 1998]. Procoagulant status, manifested in increased levels of D-dimers on the background of lipid transport disorders contributes to repeated coronary thrombosis in patients with myocardial infarction [Moss A.J. et al., 1999].

Long been known forthe negative role ofsmokingin the genesis ofvascular lesions. At the same time, manyofthe pathogenetic mechanismsplay a rolealso the suppression ofreleaseof tissue activator offibrinolysis.Laststimulatesrapid release oftissue plasminogen activatorfrom thevascular endothelium. Otherwise, there are increasedthe possibilityof thrombosisof arteries[Newby D.E.et al.,1999].
Potentialrisk factor for atherosclerosisis an increase inhomocysteine ​​levelsoccurringduring the metabolism ofmethionine.Activationof this processmay contribute toboth geneticmutations andlack of folicacid and vitaminsB6 and B12. There is possiblerole of lack ofcoenzymere-converting chomocysteine​​to methionineorcystathionine also [Greenlund K.J.et al.,1999].

Lipid deposition in the vessel walls may begin as early as adolescence, as evidenced by the yellowish color of the vascular intima. By the age of 30 there are about half the surface of the aortic intima covered by these fatty deposits in the form of yellowish stripes. These changes will not narrow the lumen of blood vessels and do not manifest clinically. In the future, these fatty layers may disappear, but in their place there are appeared fibrous plaques that can already produce symptoms of circulatory disorders. Occlusion developed in necrosis, calcification and fibrous plaques in their places of thrombosis formation [Gerrity R.G., Antonov A.S., 1997].

In all these cases the leading mechanism for the development of the disease is the accumulation of atherogenic and other biologically active factors in which drug therapy is virtually powerless. Known effect is achieved with statins, but we must remember that in such cases, the risk of developing breast cancer increases 12 times. In addition, the lipid-lowering effect of statin treatment leads to complications such as increased activity of liver transaminases several times and rhabdomyolysis with increase creatinine phosphokinase (CPK) [Lepaev Y.V., Efremova T.I., 2008].  It should alsobe noted that thedrug treatmentof patientswith elevated levels ofLp (a) is ineffective at all, and for patients withliver diseasesandallergiesareevendangerous[Konovalov G.A.et al, 2009]. Therefore, most often treatment is limited tosymptomatic therapy, aimed at expandingthe narrowedvessels. There are the samededicated andsurgicalmethods of treatmentwith atheroscleroticocclusivevascular disease.
However, only the efferent therapy, mainly plasmapheresis, seems truly pathogenic. Given sufficiently slow rate of reproduction and accumulation of atherogenic products and, especially, the presence of autoimmune mechanisms of the pathogenesis of atherosclerosis, periodic courses of such therapy allow you to maintain an acceptable level of pathological products and more stable remission, especially in cases where there were not yet irreversible organic circulatory disorders [Konovalov G.A. et al, 1998; Gavrilov O.K. et al., 1999; Chebyshev A.N. et al., 2004]. In these cases justified preventive courses of plasmapheresis in conjunction with UFO blood up to two times per year.

In cases oftoxichepatopathyon backgroundstatin therapyuseplasmapheresiscourses with Reamberinasplasma substituteled toa significant reduction intransaminaselevelsto nearlybaseline with normalizationof health andclinical parameters[Lepaev Y.V.,EfremovaT.I.,2008]. 
Hyperlipidemicpatients withcoronary artery diseaseprovides substantial assistancefor periodicsessionsof plasmapheresisfollowedplasma-immunosorptionusing specialcolumns"LDL Lipopak" [Konovalov G.A.et al., 2008, 2009]. Promising results were obtained using columns "Sferotsell LP- M" [Sokolov A.A. et al., 2002]. Good results have been achieved by the removal of LDL with the use of special columns based on dextran sulfate, which is passed through the plasma obtained by plasmapheresis [Bambauer R. at al., 2000; Kamimura M. et al., 2002]. At elevated levels of lipoprotein (a ) [Lp (a )] with normal LDL is more expedient to use special columns "Lp (a) Lipopak " (POKARD, Russia), which leads to a decrease in Lp (a) averaged 80% [Afanasyeva O.I. et al., 2002]. Aftera single sessionlipoproteinapheresis in24 hoursobservedreduction ofLp (a)by 51.1%, LDL–by 54.6%, HDL –  17%, apolipoprotein B–39.2%, ejection fractionincreased fr om64.89% to 67.07%. After 96 hours,these parameterswere restored, but still did not reachthe initial level[Bohl S.et al.,2009].
In the case ofacute pancreatitisinducedhyper-triglyceridemiaplasmapheresisallowedto reduce the concentrationfrom5430mg/dlto 403mg/dl[Nakagawa M.et al.,2008].
In cases wh ere the use of fibrinolytic therapy (streptokinase) on 4-6th day there is the development of hypercoagulability, which can be stopped after 2-3 sessions of plasmapheresis. This significantly decreases the level of fibrinogen and fibrin monomer complexes [Hoffmann E., 2003]. Intensive plasmapheresis can be applied as a separate treatment of thrombus, including thrombosis in the acute stage, and the conditions of the thrombolytic therapy also.

Perhaps the use of adsorption columns of dextran-sulfate cellulose [Yokoyama S. et al., 1985; Kojima S., 2001].

The most effective in improving the rheology and microcirculation is cascade plasma filtration when received by one of the methods of plasma passed through custom  micropore filter which passes only low molecular weight proteins (albumin) and detain macromolecular, including atherogenic, lipoproteins [Klingel R. et al., 2003; Konovalov G.A., 2009; Bosh T., Wendler T., 2004]. Cascade plasmapheresis reduces the concentration of total cholesterol by 67%, LDL by 72%, Lp (a) – 70%, triglycerides –  54% and HDL by only 30% [ Konovalov G.A. et al., 2009]. V.M.Kreyneset al.(2009) show that using acascade plasmapheresispossiblerapidand substantialreducethe severity ofhyperlipidemia,andcontinuingthrough3 weeksafter theprocedure–atherogenicratiodecreasedby 28%due to lowerLDL cholesterolby 37.3% while increasing HDL cholesterolby 10.4%.Applicationtermo-filtrationwith increasing temperatureup to38oCseparates the plasmafurther increasesthe removalof LDL andHDLreduces losses[Klingel R.et al.,2004; Krebs A. et al.,2004].

However, given a sufficiently largevariety ofaccumulating pathological products–lipoproteins,apoproteins, cholesterol, triglycerides, lipid peroxidation products, medium weightoligopeptides, kinins, circulating immune complexes, and also possiblysomeautoantibodies, enoughfull therapeuticeffectcan be expectedfrom even conventionalplasmapheresiswhenfromplasmaremovedby 100% all those initproducts. In thepatient's bloodcholesterol levelis reduced by 25%, triglycerides –10%of fibrinogen–18%with a significantimprovementof clinical parameters[Kazakov F.I.et al., 2008]. It should be emphasizedthatthe authorshave used techniquesplasma exchange with cryo-sorption of autoplasmanote that thereal increase inthe efficiency ofremoval ofcholesterol andatherogenic lipoproteinscompared to conventionalnon-selectiveplasmapheresiswas not aspronounced asitwas previously thought[Sokolov A.A. et al. 2007].
One of the additionalindications forplasmapheresisin patientswith dyslipidemiais the development ofrhabdomyolysiswithstatinsmanifestedmyalgia, myopathy, muscle weakness, a tenfoldincrease increatinine phosphokinaseactivity, increased levels ofcreatinine andmyoglobin [Konovalov G.A.et al., 2009].
Plasmapheresisismore indicatedin patientswith atherosclerosisand diabetes mellitus. Significantlyimprovedperipheral blood flowin the lower extremities also, especially in patients withdiabetic angiopathy. Aneurysmof the abdominal aortaandmultifocalatherosclerotic lesionsof major vesselsplasmapheresishas helped reduce theprothrombinandthrombin time, spontaneousplatelet aggregationand fibrinolysis, as well as blood viscosity[Mukhamadeyev I.S., 2005].
Positive resultsin lesions ofthe peripheral vesselsalsoreachedlaser(HeNe or infrared) irradiation of blood[Logvinov N.L.,SamoilovaE.V., 1999; SokolovE.I. et al., 1999; ShanoV.N.et al., 1999]. Founda pronounced therapeuticeffectof intravascular(as intravenousandintra-arterial) laser irradiation of bloodin patients withobliterativeprocessesin the vesselsof the lower limbs, allowing2-3 timesto increase the distancethat can elapsebefore thepatient ispainin the muscles. After laser irradiation improves collateral circulation with the onset of warming feeling in the distal extremities. It was able to achieve healing of local necrotic ulcers on the toes or achieve faster demarcation departments with irreversible damage to a leaner amputation [Galinzyanov F.I., 1996; Losev R.Z., Tsarev O.A., 1998; Yaitsky N.A. et al., 2006]. It is noted that laser irradiation of blood prevents deterioration of capillary blood flow during the upcoming discrete plasmapheresis [Marchenko A.V. et al., 2003]. In addition, after the photo-hemotherapy significantly improved some functional parameters such as erythrocyte deformability and aggregation properties of the normalization of the aggregation state of their membranes [Efimov A.S. et al., 2004].

Positive effect in the treatment of obliterating atherosclerosis of the lower extremities is provided during hemosorption also [Perepelitsa V.N., 2007]. Performing of regular sessions with LDL-apheresis every 2 weeks in parallel with the simvastin was much more effective than using only the drug. This prevented the progression as well as coronary and peripheral stenoses of lower limb arteries [Kroon A.A. et al., 1996].

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