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The role of the endothelin system in development of hypertension and hypertensive end-organ damage in Ren-2 transgenic rats
Opočenský, Martin ; Červenka, Luděk (advisor) ; Neckář, Jan (referee) ; Widimský, Jiří (referee)
The role of the endothelin system in development of hypertension and hypertensive end- organ damage in Ren-2 transgenic rats Endothelin-I (ET-I) has been described as one ofthe most powerful vasoconstrictors, that also play a role in the regulation of renal hemodynamics. ET system plays an important role in the pathogenesis of salt-sensitive models of hl'pertension. The benefícial effects of ET receptor blockers in modulating target-organ damage arise rrom their antiproliferative action. There is, however, a large discrepancy in the effect of ET between various models of hypertension. The hypertensive rat strain transgenic for the mouse Ren-2 (TGR) renin gene is a valuable monogenetic model of renin-dependent and thus angiotensin lI(Ang ll) - dependent hypertension, which exhibits typical signs of fulminant hypertension,i.e. reduced glomerular fíltration rate and proteinuria associated with g1omerulosderosis. Moreover, it carries a salt- sensitive component. We have recently found that nonselective endothelin ETA/ETB receptor blockade markedly improves survival rate and ameliorates end'-organ damage in malcTGR without lowering blood pressure. Because activation ofthe ETA receptor may be responsible for the detrimental effects of ET in the development of hypertension, our study was performed to...
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Interactive Influence of Genetic Effects and Effects of External Environment on Properties of Large Arteries in Relation to Sodium Management
Seidlerová, Jitka ; Filipovský, Jan (advisor) ; Widimský, Jiří (referee) ; Segers, Patrick (referee) ; Herijgers, Paul (referee)
In line with Guyton's work, the goal of our research was to explore in three European populations whether the properties of large arteries are associated with renal sodium handling, which itself changes with environmental factors and with variation in a large number of genes. Before engaging in the genetic analyses proper, we first studied the familial aggregation and the heritability of arterial properties. In all our analyses, we accounted for relatedness among participants and for covariables and confounders. In a first study, we compared the arterial characteristics and blood pressure (BP) in normotensive offspring of two normotensive parents (OFF/NT) and normotensive offspring, who had at least one hypertensive parent (OFF/HT). We measured peripheral pulse pressure (PPp) by conventional and 24-h ambulatory BP. A SphygmoCor device was used to determine the central (CAIx) and peripheral (PAIx) augmentation indexes, central pulse pressure (PPc), and aortic pulse wave velocity (aPWV). Compared with OFF/NT (n=59; 16 to 34 years of age), the OFF/HT (n=174; 17 to 40 years) had higher (0.14<P<0.0007) BP and PPp on conventional measurement (121/75 vs. 114/71 mm Hg and 46 vs. 42 mm Hg) as well as on 24-h ambulatory monitoring (118/70 vs. 114/67 mm Hg and 48 vs. 47 mm Hg). OFF/HT, compared with OFF/NT, also had...
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Genetic and molecular mechanisms of arterial hypertension in relation to chronic inflammation, oxidative stress, and chronic kidney disease
Krajčoviechová, Alena ; Cífková, Renata (advisor) ; Widimský, Jiří (referee) ; Vaněčková, Ivana (referee)
This thesis provides an appraisal of the structure of clustering of metabolic phenotypes and evaluates the pathophysiological mechanisms underlying the relationship between urinary uric acid and albumin excretion. Two population-based studies were involved. In the first part, we used data obtained in a large representative cross-sectional survey in the Czech Republic (Czech post-MONICA study). We showed that the urinary albumin/creatinine ratio (uACR) was an independent factor for an increase in serum uric acid (SUA) levels in adults without manifest metabolic syndrome (MetS), but with 1-2 MetS component(s). Furthermore, SUA levels increased by the synergistic interaction of uACR with visceral adiposity and blood pressure, which may suggest obesity-related hypertension with altered renal hemodynamics as the primary mechanism. In the second part, we analyzed data captured in a representative population sample of French Canadians (CARTaGENE study) with more detailed urine biochemical analyses available. This study yielded two novel observations. First, we showed that the rs13129697 major T allele, which has been associated with increased SUA levels in our analysis as well as in prior publications, was associated with a paradoxical decrease in uACR. The reason for this discrepant finding is the...
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Large artery properties in primary and secondary - endocrine hypertension
Rosa, Ján ; Widimský, Jiří (advisor) ; Mlíková Seidlerová, Jitka (referee) ; Špinar, Jindřich (referee)
Arterial stiffness represented by carotid-femoral pulse wave velocity (PWV) is considered to be an independent cardiovascular risk factor. This study was focused on large artery properties investigation in specific forms of hypertension using applanation tonometer Sphygmocor (Atcor Medical). PWV was significantly higher in resistant hypertension patients when compared to moderate essential hypertension (EH) patients. This difference appears to be independent of clinical blood pressure (BP). Night-time BP appears to be a more accurate predictor of PWV in EH. In another study we demonstrated that primary hyperparathyroidism (PH) (both hypertensive or non-hypertensive forms) might be associated with higher PWV when compared to EH patients or to normotensive controls and that this difference is independent of age and clinical BP. Neither calcium serum level, nor parathyroid hormone has been associated with PWV. Specific treatment by parathyroidectomy (PTX) seems to be beneficial for PWV decrease, which might be mainly determined by improved BP control after surgery. Since PTX indications for asymptomatic forms of PH have been discussed, our data suggest the potential benefit to the extent of subclinical organ damage after surgical treatment in these patients. Similarly, we prooved higher PWV in...
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Some aspects of pathophysiology of pulmonary arterial hypertension and its epidemiology in the Czech Republic
Jansa, Pavel ; Aschermann, Michael (advisor) ; Widimský, Jiří (referee) ; Čerbák, Roman (referee)
1 Univerzita Karlova v Praze 1. lékařská fakulta Některé aspekty patofyziologie plicní arteriální hypertenze a její výskyt v České republice Some aspects of pathophysiology of pulmonary arterial hypertension and its epidemiology in the Czech Republic MUDr. Pavel Jansa Praha 2011 2 Abstract Pulmonary arterial hypertension (PAH) is a group of diseases characterized by a progressive increase of resistance and pressure in pulmonary vascular bed. In all types of PAH the same four pathological processes are reported: vasoconstriction, inflammation, thrombosis and remodelling. The genetic background is essential for the development of PAH. We aimed to investigate the role of polymorphisms of endothelial nitric oxide synthase (eNOS) genes in PAH. We studied 142 PAH patients and 189 healthy subjects. We examined 3 polymorphisms of the eNOS gene, including the Glu298Asp polymorphism, 27-base pair (bp) variable numbers of tandem repeats (VNTR) and -786 T/C promoter gene polymorphism. Prevalence of 27-bp VNTR allele A was higher in patients with PAH compared with healthy controls. Patients with PAH associated with connective tissue diseases had higher prevalence of AA genotype compared with other PAH subgroups. The Glu298Asp polymorphism and -786 T/C polymorphism are not associated with PAH. Thrombotic arteriopathy is...
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Tissue microcirculation in cardiac arrest setting - impact of various methods of circulatory support
Krupičková, Petra ; Bělohlávek, Jan (advisor) ; Widimský, Jiří (referee) ; Rokyta, Richard (referee)
Introduction: This dissertation thesis aims to describe microcirculatory changes in cardiac arrest setting and to assess the impact of circulatory supports (i.e. mechanical chest compressions and extracorporeal membrane oxygenation (ECMO)) on tissue microcirculation. Methods and results: Two separate studies were designed. Microcirculation was monitored sublingually by a recent Sidestream Dark Field (SDF) technique and its parameters were evaluated offline, separately for small (of diameter ≤ 20µm) and other vessels. In order to monitor microcirculation during cardiac arrest (CA) and resuscitation (CPR) an experimental pig model was used; eighteen pigs were commenced to 3 minutes of untreated CA and subsequent 5 minutes of mechanical CPR. During CA the microcirculatory parameters deteriorated, in CPR they improved and reached 59 - 85 % of the prearrest values. The microcirculatory variables correlated neither to parameters of systemic circulation (mean arterial blood pressure and carotid blood flow) nor to lactate. In the second, clinical, study the sublingual microcirculation was monitored 29 (± 17) hours after the CA onset in 15 patients, who were after unsuccessful conventional CPR rescued by ECMO. In comparison to healthy (sex and age matched) volunteers, the patients showed mild but...
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Genetic and molecular mechanisms of arterial hypertension in relation to chronic inflammation, oxidative stress, and chronic kidney disease
Krajčoviechová, Alena ; Cífková, Renata (advisor) ; Widimský, Jiří (referee) ; Vaněčková, Ivana (referee)
This thesis provides an appraisal of the structure of clustering of metabolic phenotypes and evaluates the pathophysiological mechanisms underlying the relationship between urinary uric acid and albumin excretion. Two population-based studies were involved. In the first part, we used data obtained in a large representative cross-sectional survey in the Czech Republic (Czech post-MONICA study). We showed that the urinary albumin/creatinine ratio (uACR) was an independent factor for an increase in serum uric acid (SUA) levels in adults without manifest metabolic syndrome (MetS), but with 1-2 MetS component(s). Furthermore, SUA levels increased by the synergistic interaction of uACR with visceral adiposity and blood pressure, which may suggest obesity-related hypertension with altered renal hemodynamics as the primary mechanism. In the second part, we analyzed data captured in a representative population sample of French Canadians (CARTaGENE study) with more detailed urine biochemical analyses available. This study yielded two novel observations. First, we showed that the rs13129697 major T allele, which has been associated with increased SUA levels in our analysis as well as in prior publications, was associated with a paradoxical decrease in uACR. The reason for this discrepant finding is the...
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Aldosterone synthase in arterial hypertension and possible influence of its genenetic polymorphism on left ventricular hypertrophy
Heller, Samuel ; Horký, Karel (advisor) ; Málková, Jana (referee) ; Widimský, Jiří (referee)
Part I. The aldosterone synthase gene (CYP11B2) polymorphism T-344C in blood pressure and left ventricular hypertrophy. BACKGROUND: Aldosterone is a key cardovascular hormone, it significantly influences volume, pressure and electrolyte balance. Aldosterone plays an important role in development of left ventricular (LV) hypertrophy and myocardial fibrosis. The aldosterone synthase gene (CYP11B2) is an important candidate gene region in essential hypertension. DESIGN AND METHODS: We assessed the influence of the T-344C polymorphism of aldosterone synthase - the rate-limiting enzyme in aldosterone biosynthesis - on the structure of the left ventricle in young normotensive men. The population included 113 normotensive mid-European Caucasian men aged 18-40 years (mean 27 +/- 5 years). We also studied the association of -344T/C polymorphism of the CYP11B2 gene with the presence and severity of hypertension in 369 individuals, of whom 213 were hypertensive patients (139 controlled hypertensive, 74 resistant hypertensive) and 156 were healthy normotensive subjects. The genotype was assessed using polymerase chain reaction with subsequent cleavage with restriction enzyme HAEIII (restriction fragment length polymorphism method) and visualization with ethidium bromide. Plasma renin activity (PRA) and plasma...
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Metabolic and structural differences in primary aldosteronism and essential hypertension
Šomlóová, Zuzana ; Widimský, Jiří (advisor) ; Mlíková Seidlerová, Jitka (referee) ; Červenka, Luděk (referee)
Hypertension is a major risk factor for cardiovascular (CV) disease, and patients with primary aldosteronism (PA) - the most common endocrine cause of hypertension - have a higher incidence of CV complications. The aim of this study was to evaluate the incidence of metabolic differences and organ complications - kidney, heart and blood vessels damage in patients with essential hypertension (EH), PA and its most common forms - idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA). We found a higher incidence of metabolic syndrome and a higher incidence of metabolic abnormalities in IHA compared to APA - higher prevalence of metabolic syndrome, higher levels of triglycerides and lower levels of HDL cholesterol and thereby a higher cardiometabolic risk. Metabolic profile of patients with IHA is similar to EH in contrast to APA. Arterial stiffness was expressed as pulse wave velocity (PWV), in central arteries as carotid-femoral PWV and at peripheral level as femoral-ankle PWV. Patients with PA with comparable levels of blood pressure (BP) have higher stiffness of central elastic and peripheral muscular arteries than patients with EH. The main predictor of impaired peripheral arterial stiffness is the plasma aldosterone level. Patients with IHA have higher central arterial...
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