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New diagnostic and therapeutic approaches for the prevention of CVD in patients with familial hypercholesterolaemia
Altschmiedová, Tereza ; Češka, Richard (advisor) ; Rosolová, Hana (referee) ; Rašlová, Katarína (referee)
Atherosclerotic cardiovascular diseases are still the most common cause of death in Europe, despite new diagnostic methods and treatment. Although many accelerators of the atherosclerotic process are known, only LDL-cholesterol is considered to be the causal risk factor for atherosclerosis. Familial hypercholesterolaemia (FH) is an autosomal dominantly inherited disease whose carriers have had a high level of LDL-cholesterol since childhood due to reduced amount or function of LDL receptors . Determination of the causative mutation is not always possible and the diagnosis is established by using some scoring systems which take into account personal and family history and some typical signs (e.g. tendon xanthomas) in addition to LDL-cholesterol value. The treatment of FH is lifelong and to achieve the LDL- cholesterol target, combination therapy (ezetimibe, modern biologic therapy) in addition to statins , is often necessary. However statins are always the mainstay of the treatment. By retrospective analysis of data from 1236 patients diagnosed with FH, we confirmed the cardiovasular risk of these patients is different depending on the presence of other risk factors. At the highest cardiovascular risk were individuals with combination of risk factors - high level of LDL cholesterol and total cholesterol, as...
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Genetic factors of familial hyperlipidemia and prevention of cardiovascular diseases
Todorovová, Veronika ; Češka, Richard (advisor) ; Blaha, Vladimír (referee) ; Karásek, David (referee)
Familial hyperlipidemias are still a current cause of premature development of atherosclerotic cardiovascular disease (ASCVD). Heredity plays an important role in the development of these diseases. Genetic testing helps to specify a definite variant of a given disease and thus the degree of genetic family burden. Together with the clinical examination, it defines the exact diagnosis of the patient and reduces the risk of developing ASCVD in individual specialized care. In the theses, we focused on biochemical and genetic differences and their risk factors for the development of ASCVD in long-term monitored patients with familial hypercholesterolemia (FH), in receptor-mediated FH and familial defect of apolipoprotein B- 100 (FDB). Efficacy, safety, and tolerability of therapy were evaluated in a subgroup of FH patients with PCSK9i therapy. Furthermore, the polygenic genetic risk score (GRS) in patients with the APOE2E2 genotype and its influence on the early detection of the development of familial dysbetalipoproteinemia (FD) were analyzed. Receptor-mediated FH patients carry a mutation in LDLR while FDB patients have a prevalent mutation in APOB. LDL-C and TC levels are high in both groups, although levels are slightly higher in receptor-mediated FH patients. APOE genotype and risk factors such as...
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Hypoglycemia as a limitation of treatment of diabetes mellitus
Brož, Jan ; Kvapil, Milan (advisor) ; Češka, Richard (referee) ; Karásek, David (referee)
BROŽ, Jan. Hypoglycemia as a limitation of treatment of diabetes mellitus. Prague, 2022. 100 pages. Dissertation thesis. Charles University in Prague, 2nd Faculty of Medicine, Department of Internal Medicine. Supervisor Kvapil, Milan. In diabetes mellitus, hypoglycaemia is defined as a condition that is associated with abnormally low blood glucose levels (≤ 3.9 mmol/l), which puts the body at potential risk. The first part of the work is devoted to the treatment of hypoglycaemia associated with physical activity in patients with type 1 diabetes mellitus. The results showed that standardized moderate-intensity body movement without pre-agreed preventive measures led to hypoglycaemia in all participants. During exercise, the rate of ABG decline ranged from 0.7 mmol/l to 1.7 mmol/l in 10 minutes. During recovery after ingestion of 20 g of carbohydrates, the rate of increase in ABG ranged from 0.6 mmol/l to 1.9 mmol/l in 10 minutes. The amount of glucose administered resulted in recovery from hypoglycaemia in all study participants and maintained glycemia above this level for an additional rest period of 60 minutes after glucose ingestion. The second part of the work was devoted to comparing the characteristics of the results on the one hand of treatment in the same group of patients with type 2...
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Incidence of hyperlipoproteinemia and atherosclerotic changes in long-term survivors of Hodgkin lymphoma in childhood or adolescence
Čepelová, Michaela ; Kraml, Pavel (advisor) ; Češka, Richard (referee) ; Papajík, Tomáš (referee)
The survival of children and adolescents with Hodgkin lymphoma has improved dramatically over the last decades, but even young adult long-term survivors are at increased risk of developing multiple cardiovascular late sequelae of previous treatment. We evaluated the presence of modifiable cardiovascular risk factors (hypertension, hyperlipoproteinemia, hyperinsulinemia, obesity) in young adult Hodgkin lymphoma survivors, who were disease- free for a minimum of 10 years after the end of their treatment, and in age- and gender- matched healthy volunteers. We assumed higher prevalence of modifiable cardiovascular risk factors together with earlier development of atherosclerotic changes in this specific population. All survivors and volunteers uderwent physical examination, duplex ultrasonography of both common carotid arteries, all participants completed questionnaire on their eating habits and physical activities We performed biochemical analyses, including lipid profile, fasting glucose and insulin levels, markers of inflammation, endothelial dysfunction and oxidative stress. The HL survivors showed unfavorable lipid profiles, markers of oxidative stress, endothelial dysfunction and inflammation compared to those of healthy controls. We found a higher prevalence of insulin resistance, metabolic syndrome and...
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Metabolic aspects of the hormone replacement therapy in menopause
Fait, Tomáš ; Cibula, David (advisor) ; Češka, Richard (referee) ; Hořejší, Jan (referee)
The aim of project was to evaluate which of aplication forms of estrogen replacement therapy (in daily doses 2 mg estradiol orally or 0,05 mg estradiol transderma) is better for postmenopausal women from the view of cardiovascular risk. Oral aplication was conected with favourable elevation of HDL-cholesterol level and lowering of prothrombin activator inhibitor (PAI-1). On the other side there were elevation of tigylcerides and high selective C-reactive protein (hs CRP) and lowering of tissue factor pathway inhibitor (TFPI). Transdermal therapy was conjoined with elevation of HDL-cholesterol. Other markers were not influenced by this aplication form. Transdermal estrogen replacement therapy is more favourable than oral estrogen replacement therapy from the view of cardiovascular risks. The choice of hormone replacement therapy must be strongly individual. The knowledge of level lipids and other factors of cardivascular risk, could be helpfull during choice of aplication form, dose and contents of hormone replacement therapy.
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Variability in LPA gene transcription regulatory sequences
Zídková, Kateřina ; Češka, Richard (advisor) ; Hubáček, Jaroslav (referee) ; Freiberger, Tomáš (referee)
Charles University in Prague, The First Faculty of Medicine Thesis: Variability in LPA gene transcription regulatory sequences Name: Mgr. Kateřina Zídková Thesis Adviser: Prof. Richard Češka, M.D., Ph.D. Consulting Thesis Adviser: Assoc. Prof. Milada Kohoutová, M.D., Ph.D. Summury of Doctorate thesis Increased Lp(a) concentration is an independent risk factor for premature atherosclerosis. The Lp(a) concentration is almost entirely genetically determined with an exclusive linkage to a unique locus, the gene for apo(a), so called LPA locus. Nevertheless Lp(a) concentrations varies widely between individuals in all populations studied so far. There is a LPA gene size heterogeneity (KLPAIV type 2 repetition) accounting for 40-60% of the variance. Some of the variance could be additionally related to polymorphic sites either in the coding sequence or in transcription regulatory regions of LPA gene. We had scanned the LPA gene transcription regulatory regions (promoter, DHII, and DHIII enhancers) for variabilty. None of them was revealed to be extremely polymorphic. However significant linkage disequilibrium was detected even between polymorphic sites from far regulatory sequences. We have investigated if certain compound genotypes of apo(a) gene regulatory sequences could be associated with a narrow range of...
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Šejda, Tomáš ; Poledne, Rudolf (advisor) ; Filipovský, Jan (referee) ; Češka, Richard (referee)
Based on the results of our study, we concluded that the degree of brachial artery flow endothelium-dependent dilatation is difficult to evaluate using predefined cut-off points as a single-measurement screening test to indicate endothelial dysfunction. On the contrary, the variation of endothelial function after a defined stimulus (dietary, medication) examined at a predefined interval using an identical protocol can help to assess enhanced or reduced efficacy of endothelium-dependent vasodilatation. In the next study, we demonstrated that a high-fat load applied at a single dose does not significantly affect brachial artery vasoreactivity in young, healthy volunteers after four weeks of low- and high-fat diets. In contrast with atherosclerosis, the effect of hypercholestrolemia on adhesive molecule levels has been a source of controversy. We demonstrated that 3-month therapy with fluvastatin does not decrease cICAM-1 levels despite normalization of cholesterol levels. The implication is cholesterol may not induce endothelial activation by the initial upregulation of this adhesive molecule. Endothelial dysfunction can be considered the initial, functionally relevant stage of atherosclerosis, demonstrable still before morphological changes. In patients with advanced obliterative atherosclerosis,...
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Transportation to primary percutaneous coronary intervention is a strong independent predictor of functional status after myocardial infarction with ST elevation. Five-year follow-up of the Prague-2 trial
Mocová, Danuše ; Widimský, Petr (advisor) ; Češka, Richard (referee) ; Vítovec, Jiří (referee)
Aim. Randomized trials in ST-elevation myocardial infarction (STEMI) showed improved early outcomes after primary percutaneous coronary intervention (pPCI) compared with thrombolysis (TL). It is less known whether the early benefit is sustained during the long-term follow-up. Methods. The PRAGUE-2 study enrolled 850 patients with STEMI. The patients were randomized into two groups - transport to a primary percutaneous coronary intervention center (pPCI) (n = 429) vs. thrombolysis in community hospitals (n = 421). The data was collected from primary hospitals and PCI centers or with questionnaires. Results. The mean follow-up was 58 months. At 5 year follow-up, the cumulative incidence of composite endpoint (death from any cause or recurrent infarction or stroke or revascularization) was 53% in TL patients compared with 40% in pPCI patients (HR 1.8; 95% CI 1.38-2.33; p < 0.001). The respective cumulative incidence of recurrent infarction was 19 vs. 12 % (HR 1.72; 95% CI 1.15-2.58; p = 0.009), stroke 8 vs. 8% (HR 1.65; 95% CI 0.84- 2.23; p = 0.18), revascularization 51 vs. 34% (HR 1.81; 95% CI 1.21-2.35; p < 0.001). At 5- years, 45.4 % of patients after primary percutaneous coronary intervention vs. 31.8 % of those treated with TL were in class I of the New York Heart Association (NYHA) (HR 2.02; 95%...
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Familiar hyperlipoproteinemias and other risk factors of cardiovascular diseases in men with erectile dysfunction
Prusíková, Martina ; Češka, Richard (advisor) ; Bultas, Jan (referee) ; Rosolová, Hana (referee)
Background: The relationship between erectile dysfunction and risk factors of atherosclerosis has been confirmed by a number of previous investigations. There are also plausible pathophysiological mechanisms explaining the observed association. One of the tested hypotheses in our work was the assumption that risk factors of atherosclerosis would be more prevalent in men with erectile dysfunction than in controls selected from the representative sample of the Czech population. Our work did not confirm this hypothesis. Most likely explanation can be greater representation of younger-middle aged men in our group than in the Czech post-Monica study in which the age distribution was equal. On the other hand authors of the Czech post-Monica study admit worse compliance in younger participants of their survey. Nevertheless, the risk factors of atherosclerosis occur very frequently in males with erectile dysfunction. Results: In our group mean cardiovascular risk calculated according to the SCORE chart was 3.39% (±3,39). In the Czech post-MONICA study conducted between 2007 and 2008 the mean SCORE risk reached 2.47%. There was a trend, though not statistically significant, towards direct relationship between the severity of ED and the SCORE CVD risk. Asymptomatic atherosclerosis was detected in 56.25% of our study...
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Relationship of apolipoprotein E polymorfism on the functional fitness in the elderly
Šnejdrlová, Michaela ; Češka, Richard (advisor) ; Hubáček, Jaroslav (referee) ; Zadák, Zdeněk (referee)
(EN) Background: The life expectancy is defined by a combination of genotype (25%) and environmental influences, including lifestyle (75%). Nevertheless a stronger genetic influence is expressed in long-living individuals. Epsilon gene for apolipoprotein E (APOE) belongs among the most studied so called "candidate genes of longevity". The association of APOE polymorfism is proved in relation to many diseases (hypercholesterolaemia, cardiovascular disease, Alzheimer disease), thus we tried to evaluate the relation of APOE polymorfism and senior fitness. Methods: In our pilot study we examined a total number of 128 patients (93 women, 35 men), all of them older than 80 years, average age 88.6 ±5.3 years. Examinations: A) detailed examination of functional fitness (ADL, MMSE, Yeassavage's depression scale , MNA, 6-MWT). Based on this complex examination, patients have been sorted to 5 functional categories according to W. Spirdus, these categories objectively express the level of self - sufficiency. B) laboratory examinations C) examintaion of APOE gene polymorphism using DNA restriction analysis, DNA isolated from peripheral leucocytes Results: Our pilot study proved statisticaly significant relation (p = 0,0248) between allele E4 and functional fitness in senior age. According to the results of...
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