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Results of Approved Research Projects

Report of the Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases” on the results of the basic research program in 2015 financed by the Government of the Russian Federation within the Program for Basic Research of the State Academy of Sciences for 2013-2020

 

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Results obtained in 2015

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7. New technologies to promote healthy lifestyle, primary prevention, diagnosis and treatment of common human diseases

7.1. Cardiovascular Disease

 

A positive history of stroke, the presence of significant three-vessel disease (stenosis >50%), endothelin-1 > 1.297 fmol / l at day 10 of the in-hospital stay have been proved to be risk factors for the 1-year unfavorable prognosis of patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS).

 

The role of interleukin-10 (IL-10) gene polymorphisms G-1082A and C 592-A in the long-term prognosis of patients with NSTE ACS has been explored. CC genotype of IL-10 C592A (rs1800872) correlates with common cardiovascular risk factors, namely postinfarction cardiosclerosis, type 2 diabetes mellitus (DM), renal failure, low levels of high-density lipoprotein cholesterol (HDL), decreased production of intreleykina-10. AA genotype of IL-10 G-1082A (rs3024491) correlates with reduced renal function. CA genotype of IL-10 G-1082A (rs3024491) is associated with the 1-year unfavorable prognosis of patients with NSTE ACS.

 

The roles of polymorphisms of candidate genes in C-reactive protein (CRP) and interleukin-1 in the early onset of cardiovascular complications in patients who have undergone coronary artery bypass grafting (CABG) have been determined. The risk for perioperative cardiovascular complications increased in the presence of the factors such as: patients’ age ≥ 65 years (p = 0.037), preoperative CRP levels > 5 mg/ml (p = 0.026), identification of GG homozygous pattern in the CRP promoter region ( rs3093077) (χ2 = 9,08, p = 0.0011) in all other things being equal (presence or absence of atrial fibrillation (AF), type 2 diabetes, duration of arterial hypertension). The risk for cardiovascular complications increased in patients older than 65 years by 3-fold (OR = 2.8; 95% CI = 1.07-7.34). A 2.5-fold increased risk for cardiovascular risk was found in patients who had CRP levels > 5 mg/ml (OR = 2.5; 95% CI = 1.11-5.77). The carriers of the GG homozygous genotype in the CRP gene (rs3093077) have a 2-fold increased risk for cardiovascular complications in the postoperative period after CABG.

 

An association between inherited allelic variation in the TLR genes and coronary artery disease (CAD) have been found. The following polymorphic loci of four TLR genes were studied: TLR1 (rs5743551, rs5743611), TLR2 (rs3804099, rs5743708), TLR4 (rs4986790, rs4986791), TLR6 (rs3775073, rs5743810). The C/C genotype of the TLR1 rs5743551, the C/G genotype of the TLR1 rs5743611, as well as the T/C genotype of the TLR6 rs3775073 and the A/G genotype of the TLR6 rs5743810 strongly correlated with altered risk for developing coronary artery disease (OR = 0.41, 95% CI = 0.20 0.84, OR = 1.56, 95% CI = 1,04-2.34, OR = 1.68, 95% CI = 1.03-2.73 and OR = 1.55, 95% CI = 1.12-2.14, p <0.05, respectively), regardless of gender and age of patients.

 

A relationship between the variants at loci of innate immunity receptor genes and the development of impaired glucose metabolism in CAD patients has been determined. Carriers of the G allele of rs5743611 of TLR1 gene have increased risk for developing impaired glucose metabolism. Alternatively, carriers of the T allele of rs4986791 (Thr399Ile) and the G allele of rs4986790 (Asp299Gly) of TLR4 gene have reduced risk for developing impaired glucose metabolism (type 2 diabetes, carbohydrate intolerance). Carriers of the G/G homozygous genotype of the TLR1 rs5743611 have a 3-fold increased risk of impaired glucose metabolism at the age of 50 - 70 years. Minor A/A homozygous genotype of the TLR6 rs5743810 may prevent the development of impaired glucose metabolism in male patients.

 

The significance of the preoperative assessment of cognitive status in patients undergoing CABG has been proved as well as the significance of mild cognitive impairment (MCI) in the course of the postoperative period. According to the topographic EEG changes in the postoperative period, patients with MCI commonly showed altered theta activity in the frontal and central regions of the cerebral cortex. It may be associated with the progression of cognitive impairment and worsening social maladjustment.

 

The severity of coronary atherosclerosis is considered to be an integral index, which significantly affects the neurophysiological status of patients. The serial electroencephalographic (EEG) tracings in patients undergoing on-pump CABG during one year showed that patients with severe coronary atherosclerosis had long-term cortical dysfunction compared to patients with moderate lesions.

 

The beneficial effects of prognostic model (93.3% of probability) for developing early postoperative cognitive dysfunction in patients with type 2 diabetes who had undergone on-pump CABG have been proved.

 

Associations between high levels of galectin-3 and such cardiovascular risk factors as acute cerebrovascular accident, hypertension, a positive history of diabetes, have been identified.

 

A positive correlation between serum levels of galectin-3 and left ventricular (LV) end-diastolic (EDD) and end-systolic (ESD) dimension has been determined. An inverse correlation between serum levels of galectin-3 and left ventricular ejection fraction (LVEF) in patients with myocardial infarction has been found. Both correlations in this group of patient may reflect the severity of post-infarction remodeling.

 

of Reduced diffusing capacity of the lungs (< 80% of the predicted) in MI patients at day 14 of the MI onset has demonstrated the prognostic potential. Reduced diffusing capacity increased risk by 13.75-fold of identifying maladaptive myocardial remodeling 1 year after MI.

 

The role of stimulating growth factor ST2, a novel marker for heart failure diagnosis, in the prognosis of adverse outcomes in the in-hospital period as well as in the risk assessment for identifying maladaptive myocardial remodeling has been determined. It was found that levels of stimulating growth factor ST2 had higher diagnostic accuracy for assessing the course of MI, compared to N-terminal brain natriuretic peptide (NTproBNP). Elevated levels of ST2 at day 1 were accompanied with unfavorable course of MI: progressive angina pectoris, arrhythmias, recurrent myocardial infarction and clinical signs of acute heart failure (Killip class II-IV). The measurement of ST2 levels and NT-proBNP levels increased the diagnostic accuracy (OR 1.92; 95% CI (1.7-3.2). The quality of the model improved greatly, if both of the markers were measured in the early period of MI (sensitivity - 81%, specificity 72%, area under the curve - 0.86).

 

The factors contributing to the development of adverse outcomes in ST-segment elevation myocardial infarction (STEMI) patients with chronic obstructive pulmonary disease (COPD), who live in a large industrial region, have been determined. The factors associated with a poor short- and long-term prognosis included structural and functional changes in the myocardium and lungs, NTproBNP levels, severity of coronary artery lesions, and severity of multivessel coronary artery disease.

 

The characteristics of the progression of non-coronary atherosclerosis after myocardial infarction in patients of different age groups have been described. It was found that smoking index >50, arterial hypertension and high cholesterol significantly contributed to the progression of non-coronary atherosclerosis in patients > 60 years, whereas obesity and smoking index > 50 index - for younger patients.

 

The immediate results of CABG in CAD patients with and without of diabetes were compared. The obtained results did not differ in patients with diabetes and without it. Both groups were comparable in age and gender. The mortality rates were 1.6% and 2.0% (p = 0.682). The overall rates of cardiovascular complications were 32.3% and 28.7% (p> 0.05), respectively. The independent predictors of cardiovascular complications in diabetic patients included the presence of LV aneurysm, mitral regurgitation, decreased left ventricular ejection fraction and increased levels of glycated hemoglobin. The independent predictors of cardiovascular complications in non-diabetic patients were older age, on-pump CABG, combined surgeries, mitral regurgitation, and decreased left ventricular ejection fraction. The independent predictors of mortality after CABG in patients with diabetes were a positive history of acute cerebrovascular accident (p = 0.013) and reduced kidney function (p = 0.048), whereas in non-diabetic patients - a positive history of recurrent myocardial infarction (p = 0.029) and elevated fibrinogen levels (p = 0.024).

 

The impact of overweight/obesity and type 2 diabetes on the development of postoperative complications and in-hospital mortality after CABG has been determined. It was found that an increase in BMI was associated with high incidence of hypertension and type 2 diabetes, elevated triglyceride levels, increased left atrium size, low HDL levels and decreased glomerular filtration rate. Thus, the overall rate of postoperative complications and postoperative mortality were not associated with patients’ BMI. Obese patients had high incidence of AF in the postoperative period. Thus, the presence of class I-II obesity can not be regarded as an additional risk factor for CABG.

 

The contribution of visceral obesity to the development of an adverse cardiovascular prognosis in MI patients has been defined. Visceral obesity found in 70% of MI patients was associated with more severe insulin resistance, leptin/adiponectin imbalance, the development of glucose intolerance and type 2 diabetes after MI. Obesity-related parameters have been shown to have different diagnostic accuracy for predicting the risk for type 2 diabetes: visceral fat area had the highest diagnostic accuracy, whereas BMI - the lowest.

 

A correlation between the parameters of arterial and venous blood flow according to the imaging of ischemic stroke in carotid territory has been determined. The arteriovenous ratio of the cerebral blood flow has been proved to be a significant criterion for the diagnosis of venous and arterial strokes. A relationship between the arteriovenous ratio and CT perfusion parameters has been found. The prognostic model for stroke has been developed.

 

The analysis of changes in cerebral tissue perfusion using multislice computed tomography (CT) according to the on-pump CABG volume and hemodynamic parameters the in early postoperative period has been performed. The obtained results reported the presence of insignificant decrease in perfusion rate of the areas supplied by the anterior cerebral artery, the weak correlation, no matches on the brain perfusion maps, the lack of reliable changes of cognitive status. All these findings suggested the absence of the negative influence of the cardiopulmonary bypass time and aortic cross-clamp time on cerebral blood in CAD patients undergoing on-pump CABG irrespective of the duration of arterial hypertension.

 

A novel noninvasive method for measuring relative density of calcified portions of atherosclerotic plaque using MSCT has been developed and implemented. A method for calculating the relative density of calcified portions has been proposed. The obtained results suggested the presence of an association between small calcium deposits in atherosclerotic carotid plaques and plaque hemorrhage which is associated with their instability.

 

The rationale for a novel diagnostic algorithm for the prognosis of cardiovascular complications in CABG patients based on their adherence to therapy (including heart rate, total cholesterol level, blood pressure, BMI; treatment adherence estimated by the Davydov’s questionnaire) has been provided.

 

Cardiac rehabilitation with extended outpatient exercise trainings for patients who have undergone CABG has been improved. Home-based exercise trainings proved to be safe and able to increase exercise tolerance and to improve hemodynamic parameters, lipid profile, psychological and emotional status, enhancing patients’ adherence to treatment. However, they are less effective than supervised exercise trainings. Thus, the last fact suggests the need to improve the monitoring system for home-based exercise trainings.

 

We found that a three-week aerobic exercise training in patients who had undergone on-pump CABG resulted in lower severity and incidence of postoperative attention disorders and altered neurodynamics, as well as lower percentage of increased power biopotentials in theta1 and theta2, compared to the preoperative levels according to the EEG findings .

 

The evaluation of the physicians’ awareness of the medical and social assessment in coronary artery disease patients undergoing CABG has been performed. The obtained results reported the low level of knowledge of the regulations shown by physicians about patients’ referral to medical and social expertise as well as the criteria for identification of disabled persons, particularly of those, who have undergone CABG. The analysis of the CAD patients’ references to the medical and social examination after CABG reported certain violations in the reference period for medical and social examination, failure to comply with the recommended volume of examinations, and unreasonable reference of patients with mild alterations in cardiovascular system.

8. Invasive Technologies

8.1 Cardiovascular Surgery

 

The long-term results of tricuspid valve annuloplasty for functional regurgitation using a biological annuloplasty ring “NeoKor" in patients with acquired valve disease have been assessed. It was found that the use of biological annuloplasty rings "Neokor" can adequately manage intracardiac hemodynamic derangements, provide adequate function and ensure tricuspid valve coaptation in the long-term period.

 

The short- and mid-term results of valve-in-valve replacement for primary bioprosthetic mitral valve failure have been assessed. There were no cases of death and prosthesis-related complications.

 

Based on a comprehensive assessment of clinical and anatomical factors, the prognostic model for determining optimal strategies for endovascular revascularization in STEMI patients with multivessel coronary artery disease has been implemented.

 

Multivessel coronary stenting in the early period of acute myocardial infarction has been proved to be an effective and safe revascularization strategy for elderly patients.

 

30-day outcomes and 1-year outcomes of three myocardial revascularization strategies in patients with stable CAD and multivessel coronary artery disease were assessed in the HREVS trial. Hybrid coronary revascularization, multivessel stenting and CABG proved to be effective methods of myocardial revascularization in patients with stable coronary artery disease and multivessel coronary artery disease.

 

According to the randomized trial, radiofrequency ablation of left atrial ganglionated plexi did not lead to significant changes in autonomic tone compared to other ablation designs.

 

We found that coronary artery stenting in patients with acute coronary syndrome (ACS) with atrioventricular block did not increase the likelihood of pacemaker implantation in future. Thus, we have provided the rationale for its early implementation.

 

The quality of life (QoL) was assessed in patients who had undergone mitral valve replacement. We found that improved physical health in recipients of biological heart valve prostheses was closely associated with hemodynamic characteristics of the bioprosthesis (beta 1.2 ± 0.4, p = 0.001). Decreased physical health in the group of patients who underwent repeat heart valve replacement was mainly associated with age according to the multivariate analysis (beta 1.4 ± 0.1, p = 0.001). Low QoL was found in recipients of mechanical prostheses according to the mental health scores. Education of patients allows to improve their understanding of the disease, to raise their awareness of possible complications and results in adherence to prescribed behaviors and fast social adaptation.

8.8 Anaesthesia and Intensive Care

 

Hemodynamic profiles in different types of intermittent renal replacement therapy (IRRT) have been assessed. The rationale for hemodynamic safety and clinical effectiveness of different IRRT has been provided.

 

The first results of the experimental studies focused at the assessment of postconditioning treatment of myocardial injury with different pharmacological agents using the isolated heart model have been obtained. Selective effects of certain pharmacological agents on the postischemic myocardial injury have been found.

 

The microhemodynamic assessment using a laser Doppler flowmetry allows to predict with a high probability the development of cardiogenic shock in ACS patients with low cardiac output syndrome as well as to objectify the criteria for mechanical support termination.

 

The role of myeloid suppressor cells in the mechanisms of the inflammatory response syndrome and abortive course of multiple organ dysfunction syndrome has been determined.

8.10 The development of novel materials, products, medical instruments and devices for surgery

 

We proved that surfaces of polymeric nonwoven matrices produced by using the electrospinning and the high-frequency magnetron plasma discharges may be modified. This modification increases the adhesion properties, but significantly changes the physical and mechanical properties of polymeric matrices. However, it may have beneficial effects in the biomedical science, which is primarily focused on the increase of matrix biocompatibility rather than on its physical and mechanical properties.

 

New manufacturing technologies for biodegradable small diameter vascular grafts have been developed. These technologies allows to incorporate growth factors, chemoattractants and extracellular matrix proteins in the polymeric fibers using two-phase electrospinning.

 

The experimental study of hydrolytic degradation with a 6-month follow-up period demonstrated the absence of resorption of tubular polymer matrices as well as the absence of cardiotoxicity of the polymers (polyhydroxybutyrate/valerate (PHBV) and polycaprolactone) used for the matrices production.

 

Anti-adhesive activity and anti-inflammatory efficacy of biodegradable membranes based on PHBV and dexamethasone-loaded polylactide-co-glycolide copolymer implanted in the abdominal and chest cavity of laboratory animals have been assessed. The macroscopic study of explanted anti-adhesive membranes showed that the biodegradation rate in the thoracic cavity was slower compared to similar samples implanted in the abdominal cavity. The use of biodegradable membranes significantly reduced adhesion formation, particularly dexamethasone-loaded membranes (80% of laboratory animals did not have any adhesions). Moreover, obtained levels of IL-6 and tumor necrosis factor-α reliably confirmed that dexamethasone-loaded membranes caused less pronounced inflammatory response, compared to membranes based on PHBV.

 

Biodegradation rates of membranes depending on the manufacturing technologies have been measured. In vitro degradation studies of cast polymeric membranes reported that an increase in the proportion of glycolide in the copolymer with lactide (PLGA) accelerated the degradation rate of the studied samples. The fastest degradation rates were observed in PLGA samples (ratio 60:40). They fully degraded after 10 days. The addition of 30% wt PLGA 60:40 to polyhydroxybutyrate—oxy-valerate allowed to increase the degradation rate by 1.3-fold. In vivo degradation rate of the membranes produced by two-phase electrospinning using a coaxial nozzle reduced by 2-fold (intraperitoneal implantation).

 

Chemically fixed surface heparin in the suture material based on modified biodegradable polymer, PHBV, reduced the negative impact of the suture material on blood components caused by their direct contact. The suture materials composed of modified PHBV + heparin and implanted to laboratory animals did not provoke the formation of calcium deposits.

 

A novel heart valve prosthesis design for valve-in-valve implantation for degenerated heart valve prosthesis has been developed using mathematical modeling approach and has been approved experimentally. We calculated the optimal rigidity and stent geometry. Moreover, the leaflet parameters have been improved to ensure the optimal coaptation height and to achieve optimal hydrodynamic properties. The transprosthesis gradient and effective orifice area between the degenerated prosthesis and implanted valve-in-valve prosthesis were different.

9. The study of patterns and mechanisms of environmental effects, working environment (climatic, geographical, territorial, ecologic, anthropogenic and occupational factors) and living conditions on health and quality of life of the Russian population and on the development of public policy framework for the prevention, preservation and promotion of public health

9.5 Issues in Healthcare Organization and Medical Science

 

In order to improve the efficacy and safety of anticoagulant therapy in patients after heart valve replacement, a range of original approaches has been developed and implemented: the restoration of sinus rhythm in the intra- and postoperative period; the use of pharmacogenetic testing for warfarin sensitivity to guide its dosing; patient education to raise their awareness of the disease and to increase adherence to treatment. This multidimensional approach allowed to increase the period with the target hypocoagulation range and to reduce the incidence of hemorrhagic and thrombotic complications.

 

The factors influencing the labor productivity in the research and medical centers have been determined. The survey results showed that 59% of physicians and 57% of junior medical personnel considered salary increase to be the primary factor for productivity raising, whereas 85% of nurses chose advanced professional training. Moreover, all professional groups suggested that valid work estimate was a significant factor (between 21% and 32%) able to influence on the labor productivity.

 

The role of the quality management system (QMS) in the resource management of research and medical centers has been identified. The QMS has been proved to increase the efficiency of monitoring processes for medical and research equipment performance, the organization of its maintenance and metrological control to ensure rational and efficient use of equipment, improve the quality of medical care and research activity.

 

Cardiovascular disease (CVD) prevalence and mortality on the regional level, including climatic, social, professional and ethnic factors, have been reported. Over the last decades, mortality attributable to circulatory system disease has decreased. Mortality from coronary artery disease has massively decreased, whereas mortality from cerebrovascular disease has demonstrated low dynamic potential, compared to other regions in the Russian Federation. Cardiovascular mortality ranking in the regions of the Russian Federation has been performed. Rank differences in the all-cause mortality and cardiovascular mortality among 81 constituent entities of the Russian Federation in 2012, compared to those in 2006, were grouped into 10 similarity clusters, reflecting the main regional trends in the Russian Federation.

 

The patterns of cardiovascular risk formation in the population, depending on the social and occupational risk factors, have been determined. The prevalence of arterial hypertension in the occupational groups negatively correlated with working conditions (heavy labor, general class of working conditions, coal mining industry) indicating the presence of the occupational selection. Changes in arterial hypertension prevalence were accompanied by a unidirectional change in the age structure and the prevalence of obesity in the occupational groups, suggesting that the professional selection considered the general changes in the workers structure depending on the functional capacity and health affected by the production factors. The methodologic approaches to eliminate the influence of the professional selection according to the preliminary data allowed to optimize occupational risk assessment of arterial hypertension. By the example of the Kemerovo region, we found that age, gender, social and economic peculiarities of the population determined the prevalence of cardiovascular disease risk factors, which, in its turn, contributed to the differences in the population risk of CAD.

 

The risk factors for developing arterial hypertension in the Shors population included age, impaired glucose tolerance (IGT), obesity, (including abdominal), low physical activity, impaired lipid metabolism. Unfavorable genotypes correlated with the risk factors for CVD and arterial hypertension have been determined: the ACE ID genotype and the ADRA2B DD genotype were associated with obesity, the MTHFR TT genotype and the eNOS 4a/4a genotype - with fasting glucose, the ADRB1 AA genotype – with IGT and arterial hypertension. Renin-dependent hypertension in the Shors population was associated with younger age, severe structural and functional cardiac alterations, including increased LV mass index, whereas volume-dependent hypertension - with the middle age and an increased intima-media thickness. Left ventricular hypertrophy (LVH) was associated with a duration of hypertension >10 years, smoking, dyslipoproteinemia. The relationships between the ACE II genotype and the ADRB1 AG genotype and the development of left ventricular hypertrophy in hypertensive patients have been determined. The incidence of renal failure in the Shors population was 8.61 %. The presence of renal failure increased the risk for developing hypertension by 2 fold.

 

Medical and social aspects of long-term survival of MI patients were studied. Clinical and medical institutional predictors of recurrent myocardial infarction were assessed. The highest risk of death was associated with the first year after myocardial infarction. The one-year survival after myocardial infarction was 74.9%, the three-year survival - 62.2%, and the five-year survival - 53.8%. Circulatory system disease (88.2%) were the leading cause of death. The prevalence of cancer was 7.1%, internal diseases - 4.1%, and external causes - 0.6%. The main health and social factors reducing the long-term survival were older age, unemployment, non-performance of percutaneous coronary intervention in the in-hospital period, recurrent MI, whereas among patients of working age - the male gender.

 

The joint impact of environmental factors, namely changes in ambient air pollution concentrations, and air temperatures on cardiovascular disease indicators in the urban population has been assessed. The incidence, hospitalization rate and mortality from cardiovascular disease were directly associated with high ambient air pollutants levels: particulate matter (6.7% of the samples), hydrogen fluoride (6.6% of the samples) and formaldehyde (3.8% of samples), but inversely related to the air temperature. 16% -57% of all cardiovascular disease cases were closely related to the studied environmental factors.

 

Beneficial effects of innovative clinical and organizational technologies in the prevention of circulatory system diseases have been proved.

 

We studied epidemiological, medical and social factors contributing to the development of congenital heart disease (CHD) in children from the Kemerovo region. The most significant causes of CHD have been determined. Their contributions to the development of different CHD types have been assessed.

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