Search

The review is a brief historical insight into the study of myocardial infarction, in which the main discoveries are analyzed that have played an important role in improving the diagnosis and treatment of the disease. A special place in the review is occupied by the work of the outstanding cardiologist and health care organizer E.I. Chazov. More than the half - age, E.I. Chazov investigated various aspects of myocardial infarction, organized a system of medical care for heart attack at all stages. Many studies E.I. Chazov are recognized worldwide.Обзор представляет собой краткий исторический экскурс изучения инфаркта миокарда, в котором описаны основные открытия, сыгравшие важную роль в улучшении диагностики и лечения заболевания. Особое место в обзоре занимают работы выдающегося кардиолога и организатора здравоохранения Е.И. Чазова. Более полувека Евгений Иванович Чазов посвятил исследованию различных аспектов инфаркта миокарда, организовал систему медицинской помощи при инфаркте на всех этапах. Многие исследования Е.И. Чазова имеют мировое признание.

In search of genetic markers of myocardial infarction (MI) risk, which have prognostic significance for Russians, we performed a replication study of MI association with genetic variants of PCSK9 (rs562556), APOE (epsilon polymorphism, rs7412 and rs429358), LPL (rs320), MTHFR (rs1801133), eNOS (rs2070744), and the 9p21 region (rs1333049) in 405 patients with MI and 198 controls. Significant MI association was observed with variants of the lipid metabolism genes (PCSK9, APOE and LPL), and of eNOS. The SNPs in the MTHFR gene and the 9p21 region were not significantly associated with MI one by one but were included in several different MI-associated allelic combinations identified by multilocus analysis. Since we have not revealed nonlinear epistatic interactions between the components of the identified combinations, we postulate that the cumulative effect of genes that form a combination arises from the summation of their small independent contributions. The prognostic significance of the additive composite model built from the PCSK9, APOE, LPL, and eNOS genes as genetic markers was assessed using ROC analysis. After we included these markers in the previously published composite model of individual genetic risk of MI, the prognostic efficacy in our sample reached AUC = 0.676. However, the results obtained in this study certainly need to be replicated in an independent sample of Russians.

Platelets bearing leukocyte antigen CD45 were identified in the blood of patients with myocardial infarction (MI) and healthy donors by flow cytofluorimetry. Part of these platelets contained tissue factor (TF)-primary initiator of blood clotting. The number of CD45+ and CD45+/TF+ platelets in MI patients at the first day was comparable with their level in healthy donors, but was increased at 8-12 days after MI onset. At that time in some patients the amount of CD45+ and CD45+/TF+ platelets reached 5-6 and 2-3% of their total number. It is assumed that CD45+/TF+ platelets could be formed as a result of platelet interaction with leukocytes or leukocyte produced membrane microparticles.

to elaborate a complex model for myocardial infarction (MI) risk assessment considering the combined effect of genetic predisposition, age and smoking.The study included two independent samples of ethnic Russians: 325 patients with MI and 185 individuals without history of cardiovascular diseases (controls) from the Moscow region, and 220 patients and 197 controls from the Republic of Bashkortostan. Genotyping of polymorphic loci of genes CRP (rs1130864), IFNG (rs2430561), TGFB1 (rs1982073), FGB (rs1800788) and PTGS1 (rs3842787) was performed. To construct the predictive models, we used logistic regression with stepwise inclusion of variables. The predictive value was evaluated by the area under the curve (AUC) in a ROC-analysis. The factor was considered as a marker at pAUC0.05 calculated by the method of DeLong. The marker was considered effective at AUC0.60.Three separate genetic variants FGB rs1800788*T, TGFB1 rs1982073*TT, CRP rs1130864*TT, and biallelic combination IFNG rs2430561*A + PTGS1 rs3842787*T whose association with MI we described earlier, were used to construct the composite genetic marker (AUC=0.66 in the training and test samples) by the logistic regression method. Adding to the obtained composite genetic marker such parameters as age and smoking allowed to create a complex MI risk marker, which was characterized by the predictive value stability (AUC=0.77 in the training sample and 0.82 in the test sample).The obtained complex model for MI risk assessment was reproduced in two independent samples of Russian ethnicity individuals from different regions of Russia with different gender identities, and allowed to have a reasonable chance (about 80%) of distinguishing patients and healthy individuals.

Increased mean platelet volume (MPV) is an independent risk factor of thrombotic events in patients with cardiovascular diseases. Interactions of MPV with platelet aggregation activity and contents of glycoprotein (GP) IIb-IIIa (aIIb/b3 integrin, fibrinogen receptor) and GP Ib (von Willebrand factor receptor) were investigated in this study. Investigation was performed in a group of healthy volunteers (n = 38) and in a group of patients with acute coronary syndrome (ACS). In patients blood was collected at days 1, 3-5 and 8-12 after ACS development. As an antiaggregant therapy all patients received acetylsalicylic acid (ASA, inhibitor of thromboxane A2 synthesis) and most of them – clopidogrel (ADP receptor antagonist) with the exception of part of the patients (n=44) at day 1 who had not taken clopidogrel before first blood collection. In volunteers platelet aggregation was stimulated by 1.25, 2.5, 5 and 20 M ADP, and in patients – by 5 and 20 M ADP. GP IIb-IIIa and GP Ib content on platelet surface was measured using 125I-labelled monoclonal antibodies. GP IIb-IIIa and GP Ib genetic polymorphisms were determined in ACS patients. In healthy donors significant correlations between MPV and aggregation levels were revealed at 1.25 and 2.5 M ADP (coefficients of correlation (r) - 0.396 and 0.373, p0.05). Correlations between MPV and aggregation levels were observed at day 1 of ACS in a subgroup of patients who received ASA but had not started clopidogrel treatment (r - 0.526, p

Carriage frequencies of alleles and genotypes of the TGFB1 gene polymorphous loci -509C>T (rs1800469), 869T>C (rs1982073), 915G>C (rs1800471), which affect the level of cytokine TGF-β1 production, were analyzed in the patients of Russian ethnic descent with myocardial infarction (MI) (406 cases) and in the control group of the same ethnic descent (198 controls). Significant association with MI was observed in car- riage frequencies of the allele TGFB1*-509T (p=0.046, OR =1.45, 95% CI: 1.02-2.06), genotypes TGFB1*869T/T (p=0.0024, OR =1.75, 95% CI: 1.22-2.51), and TGFB1*915G/G (p=0.048, OR=1.76, 95% CI: 1.05-2.97). Linkage disequilibrium analysis for these SNPs has shown that the associations revealed can be considered to be inde- pendent. A complex analysis of MI association with combinations of alleles/genotypes of said SNPs indicates their cumulative effect. An analysis of susceptibility to early-onset MI (≤ 50 years old) revealed a positive asso- ciation of the allele TGFB1*-509T (p=0.002, OR=2.24, 95% CI: 1.35-3.71) and genotype TGFB1*869T/T (p=0.008, OR=1.93, 95% CI: 1.18-3.15), as well as their additivity. An analysis of susceptibility to recurrent MI revealed an association of the genotype TGFB1*-509T/T (p=0.0078, OR=2.60, 95% CI: 1.28-5.28). The results obtained indi- cate the important role of the TGFB1 gene in susceptibility to MI, including early-onset and recurrent MI, in Russians. KEYWORDS myocardial infarction; Russians; genes; allelic polymorphism; transforming growth factor β1; TGFB1; APSampler. ABBREVIATIONS dNTP - deoxynucleoside triphosphate; LD - linkage disequilibrium; SD - standard deviation; SNP - single nucleotide polymorphism; TGF-β1 - transforming growth factor beta 1; TGFB1 - gene encod- ing transforming growth factor beta 1; CI - confidence interval; IHD - ischemic heart disease; MI - myocar- dial infarction; OR - odds ratio; PCR - polymerase chain reaction; PCR-SSP - polymerase chain reaction with sequence-specific primers; CVD - cardiovascular diseases.

Glycoprotein (GP) IIb-IIIa (αIIbβ3-integrin) is the central receptor of platelet aggregation. Activated GP IIb-IIIa binds fibrinogen or von Willebrand factor, which forms molecular bridges between aggregating platelets. This review summarizes data on the relationship between GP IIb-IIIa expression on the platelet surface and platelet aggregating activity. GP IIb-IIIa number, measured as maximal binding of complex-specific monoclonal antibody, varied by approximately two fold in both healthy volunteers (n = 35) and patients with acute coronary syndrome (ACS) (n = 65). In healthy volunteers positive associations were observed between GP IIb-IIIa number and the level of ADP-induced aggregation when this relationship was analysed in untreated platelet-rich plasma (PRP) as well as upon in vitro addition of aspirin or non-saturating concentrations of GP IIb-IIIa blockers. In the same group of volunteers almost no differences in aggregating activity were detected between donors carrying the GP IIIa Pro33 allele (n = 15) and those with the GP IIIa Leu33Leu33 genotype (n = 20). No significant relationships were revealed between platelet aggregability and variations of plasma fibrinogen concentration. Positive correlation of the level of ADP-induced aggregation and GP IIb-IIIa content was detected in patients with ACS within the first hour upon admission to the hospital when they had already received aspirin, but not clopidogrel. However, there were no correlations between these parameters at days 3-5 and days 8-12 (before discharge). At these time points patients were treated not only with aspirin but were saturated with clopidogrel as well. In ACS patients we also evaluated the expression of another platelet adhesive receptor, GP Ib, and found a significant positive correlation between GP IIb-IIIa and GP Ib content. A strong association was also revealed between the number of both receptors and mean platelet volume. The latter observation indicated that individual variations of the number of glycoprotein molecules are mainly affected by platelet size but not the density of their expression on the platelet membrane. Possible usefulness of measuring GP IIb-IIIa content as a marker of increased platelet reactivity is discussed.

Takotsubo cardiomyopathy is an acute cardiac syndrome that mimics ST segment elevation myocardial infarction. It is characterized by transient local contractility disturbances as akinesis of the apical and middle segments of the left ventricle concurrent with hyperkinesis of its basal portions in the absence of significant coronary artery changes. A description of 2 clinical cases and a review of literature on this rare myocardial disease are given.

Frequencies of the carriership of alleles and genotypes of functionally important polymorphous loci of some inflammation genes (proinflammatory cytokine genes IL-6, LTA, and TNF; anti-inflammatory cytokine gene TGFB1; and CC chemokine receptor 5 gene CCR5) were analyzed in 199 ethnic Russian patients with myocardial infarction (MI) and in a control group of 142 persons of the same ethnic descent. Complex analysis by the APSampler algorithm revealed associations of MI with the carriership of all polymorphic variants either regarded as individual risk factors (insertion-deletion polymorphism of CCR5 and SNP G252A LTA) or in combination with other alleles or genotypes. The carriership of bi-or triallelic combinations was associated with MI more reliable than the carriership of any subsets: single alleles or allele pairs. The protective triallelic combination d*CCR5 + 252G*LTA + -174C*Il-6 was found to be the most significant (p = 0.0006, OR = 0.23, CI = 0.090–0.56). Separate analysis of genetic susceptibility to MI in men and women demonstrated sexual dimorphism for the CCR5 gene.

Spontaneous platelet aggregation was evaluated in patients with acute coronary syndrome on days 1, 3-5, and 8-12 of the disease. On day 1, aggregation was analyzed after aspirin, but before clopidogrel administration; during other periods after both antiaggregants. The mean levels of spontaneous aggregation after antithrombotic therapy did not change during different periods after the onset of acute coronary syndrome, in contrast to ADP-induced aggregation that decreased after the development of clopidogrel effects (days 3-5 and 8-12). Spontaneous aggregation during different periods directly correlated (r>0.4, p

Glycoprotein (GP) llb-llla anagonist monafram is the F(ab)2 fragments of anti GP llb llla monoclonal antibody FraMon (CRC64). Efficacy and safety of monafram in primary coronary angioplasty of patients with acute coronary syndrome without ST segment elevation (non ST ACS) was evaluated in this study. Monafram was introduced intravenously to 284 patients just before angioplasty at standard dosage - 0.25 mg/kg as single i.v. bolus. Control group included 203 patients. All patients received aspirin (loading dose 300 mg and then 75 mg daily) and more than 90% - clopidogrel (loading dose 300-600 mg and then 75 mg daily). Within 30 days of follow up period monafram decreased by more than 2.5 fold the total amount of unfavorable outcomes (cardiovascular death, myocardial infarction and indications for repeat revascularization due to angina recurrence) - from 19.2% to 7.4% (p0.001). The rate of indications for revascularization was most strongly decreased - by more than 7 times - from 7.9% to 1.1% (p0.001). The number of myocardial infarctions was reduced by more than 2 times - from 8.4% to 3.9% (p=0.057). The amount of lethal outcomes did not differ between two groups (2.9% and 2.4% in the control and monafram groups, respectively). In the control group 8.9% patients received monafram during primary angioplasty due to urgent indications. Monafram did not cause any allergic reaction in all tested patients. Major bleeding was registered in one (less than 0.5%) and deep thrombocytopenia (20000 platelets per 1 ul) - in 3 (1.1%) out of 284 patients. The data obtained indicated that monafram decreased the number of thrombotic complications in non ST ACS patients undergoing angioplasty upon the dual antiplatelet therapy (aspirin+clopidogrel) and without significant increase of dangerous side effects.

The purpose of the study was to evaluate safety, effects on platelet aggregation and pharmacokinetics of F(ab')(2) fragments of anti-glycoprotein (GP) IIb-IIIa murine monoclonal antibody FRaMon (F(ab')(2) FRaMon) upon its intravenous administration in patients undergoing high-risk coronary angioplasty. Patients were treated before angioplasty with F(ab')(2) FRaMon at 0.2 mg/kg (n = 17) and 0.25 mg/kg (n = 12) bolus or with abciximab at 0.25 mg/kg bolus + 12 h infusion at 0.125 microg/kg per min (n = 29). F(ab')(2) FRaMon at both doses decreased platelet aggregation induced by 20 microM ADP to10,20,40 and70% of the predrug level at 1, 12, 24 and 72 h after injection, respectively. No significant differences were observed between F(ab')(2) FRaMon and abciximab antiaggregatory effects. In none of the patients did F(ab')(2) FRaMon cause allergic reactions, major bleedings or deep thrombocytopenia. Antibodies against F(ab')(2) FRaMon were detected in one patient. Free F(ab')(2) FRaMon was cleared from plasma within 12 h, while platelet-bound preparation occupied95, 70-80 and 40-50% of GP IIb-IIIa at 1 and 12-24 h and 3 days after injection, respectively. Thrombotic complications within the first month after angioplasty in groups treated with F(ab')(2) FRaMon and abciximab were observed in one and two patients, respectively. The data obtained have shown that F(ab')(2) FRaMon at bolus administration to patients undergoing coronary angioplasty caused no serious side effects and at comparative dosage inhibited platelet aggregation with the same efficacy as abciximab at bolus + infusion administration.

Calcium antagonists exhibit direct antiatherosclerotic action in primary culture of human aortic atherosclerotic cells by lowering intracellular lipid content, proliferative activity and synthesis of the extracellular matrix. Verapamil exhibited the highest efficacy in this respect. New calcium antagonist, anipamil, and its enantiomers have been tested in cell culture. At 10-6 M and higher concentrations, anipamil and its enantiomers produced considerable decrease in intracellular contents of cholesteryl esters, triglycerides and free cholesterol, suppressed cell proliferation and inhibited synthesis of the extracellular matrix. The efficacy of anipamil enantiomers and racemate was similar to that of verapamil. Blood plasma obtained from patients after administration of 80 mg verapamil or 20 mg nifedipin significantly lowered the cholesterol content of cultured cells. Blood plasma of most atherosclerotic patients possesses atherogenic properties, i.e. it is able to increase cholesterol content in cultured cells. Plasma atherogenicity manifested in culture decreased considerably or even disappeared after both nifedipine and verapamil administration. After 28 days of nifedipine therapy, plasma atherogenenicity was lower compared with the initial value at the beginning of the treatment. These observations suggest that control of plasma atherogenicity after drug administration may provide an additional tool for optimization of direct antiatherogenic and antiatherosclerotic therapy.

It has been shown that calcium antagonists suppress experimental atherosclerosis in animals (1). Recently it was demonstrated that nifedipine and verapamil suppress the development of human coronary atherosclerosis and induce regression of atherosclerosis in patients (2.3). The mechanisms of antiatherogenic (preventive) and antiatherosclerotic (leading to regression) actions of calcium antagonists remain obscure.

A study was made of the mechanism and products of ablation of atherosclerotic plaques and arterial walls by laser radiation of wavelengths 308, 539, and 1078 nm at energy densities 0.5–8 J/cm2. Visible and infrared radiation were found to have a tissue damage threshold of 3–4 J/cm2 and the process was "explosive" involving ejection of large fragments. Ultraviolet radiation resulted in "soft" ablation of tissues throughout the investigated range of energy densities with the minimal effects on the underlying layers. The specific energy of ablation in air was 1.1 ± 0.3 kJ/g and the effective quantum yield of volatile products in vacuum was 0.8 ± 0.3. The quantum yield of lipids and their photoproducts was approximately the same at all the wavelengths and did not exceed 10−3. The results obtained confirmed the photochemical mechanism of ablation of tissues by XeCl laser radiation.