Landowners’ Сolonization of Bashkiria

The “closed city” practice, exercised in Ufa province before 1735, together with the unfavourable political situation led to the bad crisis of estate landownership of the Ufa district. The population polls of the mid-XVII — beginning of XVIII cc. justify the fact that Ufa noblemen had to succumb to the fate of socially deprived Siberian nobility, practically devoid of serf peasants. The beginning of the largest-scale Bashkir insurrection of 1735–1736 made the administration review its attitude to the former ban on Bashkir estate lands sale. In the history of Bashkir landowners’ colonization the edict dated February 11th, 1736, allowing the local officers and officials to buy lands from Bashkir communities, was of principal importance. This procedure was exercised simultaneously with the establishment of the Russian government military control over the south-eastern border, separating Bashkir estate lands from Kazakh migratory tribes. From this moment on there is a stop in diplomatic contacts of the Bashkir elite with the governors of the Middle Asia, Kazakhstan and Turkey that meant the complete loss of political subjection by the Bashkirs. Bashkir communities become active participants of economic relations with Russian landowners, plant owners and the state institutions. Russian government preserved estate dynastic rights with the Bashkirs and refused from large-scale operations on the expropriation of Bashkir lands, transferring the mission of colonization to private persons, who had to arrange the issue with the local communities by themselves. The permission to sell estate lands forced landowners to active participation in the system of Russian legal relations, to contact the Russian government and customers

Determinants of exercise performance and effects of physical training incardiac patients : genetic, haemodynamic, respiratory and metabolic factors

Exercise performance, expressed as peak oxygen uptake (VO2) or aerobic power, is an independent prognostic factor in cardiovascular disease. An increase in aerobic power can be achieved through regular physical exercise. Larger increases are, furthermore, associated with greater decreases in cardiovascular mortality. Understanding the determinants of aerobic power and of its response to training in coronary artery disease (CAD) is therefore of substantial clinical relevance. There is, however, considerable individual variation in aerobic power as well as in the response to physical training in CAD, of which the larger part remains unexplained. The major aim of this project was therefore to identify determinants of exercise performance and its trainability in patients with ischemic heart disease and in cardiac patients with varying degree of left ventricular function. The research project comprised three major parts: 1. Study of the association of genetic variation in specific candidate genes with aerobic power and with the response to training in patients with CAD (Chapters 2, 3, 4 and 5). 2. Evaluation of the clinical application and the effect of physical training on the oxygen uptake efficiency slope (OUES) as a new submaximal index of exercise performance in patients with CAD (Chapter 6). 3. Determination of the effect of creatine supplementation in conjunction with physical training in cardiac patients with varying degree of left ventricular function (Chapter 7). 1. Genetic determinants of aerobic power and physical training effects in cardiac patients We aimed to identify genetic determinants of aerobic power and of the response to physical training in patients with CAD by combining methods from genetics with data from maximal exercise testing and training. A selection was made out of all Caucasian patients who had been referred to the ambulatory cardiac rehabilitation program of the University Hospitals of Leuven from 1990 through 2001 after myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting (CABG), stable angina pectoris which did not limit exercise performance, or a combination of these. Only biologically unrelated patients who had achieved evident exhaustion during graded bicycle exercise testing for the determination of exercise performance at baseline and after three months of exercise training were eligible for inclusion in the CAREGENE study “CArdiac REhabilitation and GENetics of Exercise performance”. Patients with concomitant pathology, like heart transplantation, implantation of a pacemaker, a cardioverter defibrillator or an artificial valve, or after any other cardiac surgery were excluded. A suitable blood sample was drawn from an antecubital vein in 935 patients. DNA was extracted from white blood cells and genotyping was performed to investigate polymorphisms in the: - ACE gene (Chapter 2) - muscle-specific creatine kinase gene (Chapter 3) - b1-adrenoreceptor gene (Chapter 4) - endothelial nitric oxide synthase (eNOS) gene (Chapter 5) - extracellular superoxide dismutase (EC-SOD) gene (Chapter 5) In chapter 2 the association of aerobic power and of its response to training with the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in CAD was investigated. In the entire cohort of 933 patients with CAD and, separately, in patients who did not receive ACE-inhibitors during physical training (n=688), aerobic power at baseline and after three months of training were not different among ACE II, ID and DD-genotypes or among II patients and D-allele carriers. An independent association between ACE I/D polymorphism and aerobic power response was, however, observed in the whole group and in patients who were not on ACE-inhibitor therapy. The response to physical training was larger in ACE II homozygous patients in comparison with ID heterozygotes or with D-allele carriers. There was no association with aerobic power or its response to training in patients receiving ACE-inhibitor drug therapy during exercise training. In chapter 3 the association between the NcoI ‘restriction fragment length polymorphism’ (RFLP) of the muscle-specific creatine kinase (CKMM) gene and aerobic power and the response to physical training in CAD was evaluated. Aerobic power at baseline, after three months of training and the response to physical training were not different across the CKMM GG, AG and AA NcoI genotypes. In chapter 4 we investigated whether Ser49Gly and Gly389Arg of the b1-adrenoceptor (b1AR) gene or their haplotypes are associated with aerobic power of with the response to training in CAD. In the carriers of the homozygous Gly49Gly genotype aerobic power at baseline was higher than in carriers of Ser49Ser and Ser49Gly genotypes. At baseline, aerobic power was highest in the Ser49-Gly389/Gly49-Gly389 and Gly49-Arg389/Gly49-Arg389 haplotype combinations. An association with the effect of physical training was not observed. In chapter 5 we focussed on variation in genes encoding for one or more enzymes involved in endothelial function as possible determinants of aerobic power or the response to training in patients with CAD. We first investigated polymorphisms -1495T>A, -949A>G, -813T>C, 273C>T and 894G>T (Glu298Asp) of the endothelial nitric oxide synthase (eNOS) gene. At baseline, Glu298Asp was associated with aerobic power. Haplotypes of the eNOS polymorphisms that predicted aerobic power and its response to training were identified. In chapter 5 we also investigated polymorphism Arg213Gly of the extracellular superoxide dismutase (EC-SOD) gene. After training, aerobic power was enhanced in carriers of the heterozygous Arg213Gly genotype in comparison with those homozygous for the Arg213 allele. In the former patients the response also tended to be higher. 2. Submaximal index of exercise performance: the oxygen uptake efficiency slope (OUES) In chapter 6 we studied the clinical application and the effect of physical training on a recently introduced submaximal index of cardiopulmonary functional reserve derived from respiratory data, the ‘Oxygen Uptake Efficiency Slope’ (OUES) in cardiac patients with CAD. All patients with clinically documented CAD who had achieved evident exhaustion during graded cycle ergometer testing for determination of exercise performance before (n=590) and after three months of physical training (n=425) over a 4-year-period at the cardiac rehabilitation unit of the University Hospitals of Leuven were retrospectively included. The ‘breath-by-breath’ data of these patients were used to determine OUES and other ‘classical’ submaximal parameters, such as the ventilatory anaerobic threshold (VAT) and the slope of the relation of pulmonary ventilation (VE) v carbon dioxide production (VCO2) (VE-VCO2 slope) in each patient before and after three months of physical training. OUES was determined from the relation: VO2 = a log10VE + b, where a is the OUES and b the intercept. In addition to the OUES derived from submaximal respiratory data up to a respiratory gas exchange ratio (RER) of 1.0, OUES was calculated using respiratory data from the first 90% of exercise time as well as using 100% of respiratory data plots. First, submaximal OUES, calculated up to RER=1, was marginally lower than the OUES calculated from 100% of respiratory exercise data. The applicability of submaximally derived OUES thus remains controversial. Second, submaximal OUES and VAT were positively correlated with peak VO2. The large inter-individual variations, however, between actual and estimated peak VO2 values limit the usefulness of the OUES and VAT in clinical practice as a means to predict peak VO2 in CAD. Third, OUES was impaired in patients who underwent CABG as compared with patients after PTCA with or without myocardial infarction. OUES was also impaired in patients with atrial fibrillation as compared with normal sinus rhythm and in patients with claudication. Age, gender, height and weight, myocardial infarction, CAGB, PTCA, atrial fibrillation and claudication explained 52% of the variance in OUES. Finally, peak VO2 and OUES increased after three months of physical training. Changes in peak VO2 correlated better with changes in OUES and in VAT than with changes in VE-VCO2 slope. OUES would therefore appear to be clinically useful to monitor changes in exercise performance and to examine the effects of physical training among CAD patients who can only perform submaximal exercise. 3. Creatine supplementation in conjunction with physical training in patients with varying degree of left ventricular function In chapter 7 we investigated the effects of supplementation with oral creatine (CR) in conjunction with physical training in cardiac patients with varying degree of left ventricular function. 70 patients were randomly assigned to an experimental group (CR) or a control group (placebo, PL). The investigator and the participants in this explorative study were blinded to the assignment. At baseline, left ventricular ejection fraction (LVEF) was measured by ECG-gated SPECT, aerobic power was determined during graded bicycle testing, knee extensor peak isometric and isokinetic strength, endurance and recovery were assessed by an isokinetic dynamometer, and health-related quality of life (HRQL) was evaluated by means of the SF-36 and MacNew Heart Disease questionnaires. In 16 patients, biopsies from the m. vastus lateralis were taken to determine total creatine (TCr) content. All tests were finally repeated after three months (3 sessions/wk) of cardiorespiratory endurance training and moderate resistance training. Training increased aerobic power, muscle performance, and HRQL, but to a similar extent in PL and CR. There was no effect of initial LVEF on the results. On average, muscle TCr was not increased in PL or CR. No detrimental effect on renal or liver function was observed, nor were there any reports of adverse effects in CR. LVEF was not affected by the intake of CR and remained stable in both groups. It was concluded that a combined resistance and endurance training programme is very effective in improving cardiorespiratory and skeletal muscle performance and HRQL in patients with CAD. Oral creatine does, however, not enhance the physical training response. Furthermore, the effect of CR is not dependent of LVEF at baseline.Acknowledgements, vii Chapter 1: General introduction, 11 Chapter 2: The CAREGENE study: ACE gene I/D polymorphism and effect of physical training on aerobic power in coronary artery disease: 43 Chapter 3: The CAREGENE study: muscle-specific creatine kinase gene polymorphism and aerobic power in coronary artery disease, 51 Chapter 4: The CAREGENE study: polymorphisms of the beta1-adrenoceptor gene and aerobic power in coronary artery disease, 61 Chapter 5: Endothelial nitric oxide synthase and extracellular superoxide dismutase gene polymorphisms and aerobic power response to training, 89 Chapter 6: Oxygen uptake efficiency slope in coronary artery disease: clinical use and response to training, 121 Chapter 7: The effect of creatine supplementation on the response to exercise training in cardiac patients, 151 Chapter 8: General discussion and future directions, 185 Short curriculum vitae, 223 List of publications by Johan Defoor, 224status: publishe

Changes in QRS duration are associated with maximal exercise capacity in adult patients with repaired tetralogy of Fallot

OBJECTIVE: In adult patients with repaired tetralogy of Fallot (TF) QRS duration at rest seems to be a predictor of maximal exercise. We examined the relationship between QRS duration during exercise and exercise performance. DESIGN: In 57 consecutive TF patients QRS duration in V1 (ms) was measured at rest, at maximal exercise (Wmax, W), and at peak oxygen consumption (peak VO2, ml/min). Stroke volume (SV) was calculated from cardiac output, obtained by CO2 rebreathing. Spearman rank correlation was used to describe the relationship between QRS duration and exercise performance. Statistical significance was defined as P<0.05. RESULTS: Seven patients, who didn't pass the anaerobic threshold, and one outlier (Wmax=340 W) were excluded, resulting in a sample of 49 patients (75.5% male; median age=24 years, range 16-43 years). QRS duration at rest (median=160 ms, range 78-194 ms) and at maximal exercise (median=153 ms, range 80-193 ms) did not differ significantly. The median change of QRS duration during exercise was -5 ms (range -31 to +83 ms). This was negatively correlated with Peak VO2 (2081+/-577 ml/min; rho=-0.33, P=0.02) and Wmax (182+/-53 Watt; rho=-0.33, P=0.02). In patients with QRS shortening peak VO2 and the exercise induced increase in SV were significantly higher than in patients with QRS shortening. CONCLUSIONS: This study indicates that QRS shortening during exercise in TF patients is related with a better exercise performance. Lower increase in stroke volumes may be responsible for this difference. Further research is needed to elaborate these findings.status: publishe

Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial

Objective: To investigate the effect of oral creatine supplementation in conjunction with an exercise programme on physical fitness in patients with coronary artery disease or chronic heart failure.Design: Single centre double-blind randomized placebo controlled trial.Setting: Cardiac rehabilitation centre.Subjects and intervention: 70 (4 women) cardiac patients (age 57.5 (8.4) years) were randomized to a placebo (n = 37) or creatine (n = 33) treatment for three months. Combined aerobic endurance and resistance training (three sessions/week) was performed during supplementation. MAIN MEASURES: Aerobic power was determined during graded bicycle testing, knee extensor peak isometric and isokinetic strength, endurance and recovery were assessed by an isokinetic dynamometer, and health related quality of life was evaluated with the SF-36 and MacNew Heart Disease questionnaires. In addition, blood samples were taken after an overnight fast and 24 hour urinary collection was performed.Results: At baseline there were no significant differences between both groups. We observed main time effects for aerobic power, muscle performance, health related quality of life, high density lipoprotein cholesterol and triglycerides (pre vs post; P 0.05). Further, no detrimental effect on renal or liver function was observed nor were there any reports of side effects.Conclusion: Oral creatine supplementation in combination with exercise training does not exert any additional effect on the improvement in physical performance, health related quality of life, lipid profile in patients with coronary artery disease or chronic heart failure than exercise training alone.status: publishe

The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure

The discoid form of platelets is maintained by a marginal band of tightly coiled microtubules. beta1-tubulin is the major isoform within platelet and megakaryocyte microtubules. In 24.2% of 33 unrelated inherited macrothrombocytopenia patients and in 10.6% of 272 subjects of a healthy population a P for Q substitution in beta1-tubulin was found in the highly conserved residue 43. Heterozygous carriers of the Q43P variant showed a reduced platelet protein beta1-tubulin expression. Transfection of green fluorescent protein (GFP)-tagged Q43P beta1-tubulin in megakaryocytic MEG01 cells resulted in a disturbed tubulin organization. Electron microscopy revealed enlarged spherocytic platelets with a disturbed marginal band and organelle-free zones. In addition, platelets with the Q43P beta1-tubulin variant had reduced adenosine triphosphate (ATP) secretion, thrombin receptor activating peptide (TRAP)-induced aggregation and collagen adhesion. The prevalence of the Q43P beta1-tubulin variant was also 2 times higher (odds ratio, [OR] = 2.1;95% confidence interval [CI], 1.22-3.59) among control subjects than among patients with cardiovascular disease (10.4% versus 5.2%, P < .001). By analyzing this protective factor in men and women separately, this association was only found in men. This study thus presents the functional consequences of the platelet Q43P beta1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis.status: publishe