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Remodeling of the intima-media complex of the common carotid artery and left ventricle myocardium in patients with primary and secondary hypertension
Majtan, Bohumil ; Holaj, Robert (advisor) ; Piťha, Jan (referee) ; Danzig, Vilém (referee)
Arterial hypertension ranks among the most prevalent cardiovascular disorders and represents one of the most significant risk factors for cardiovascular morbidity and mortality. Beyond hypertension itself, additional hemodynamic and neuroendocrine influences contribute to the pathological mechanisms that induce structural alterations in the cardiovascular system. Of notable importance in this process is the excessive production of aldosterone and catecholamines. The objective of the research has been to study the impact of aldosterone and catechola- mine excess on intima-media complex remodeling in the common carotid artery and left ventricular wall in primary aldosteronism (PA) and pheochromocytoma (PHEO) patients. Texture analysis of the intima-media complex of the common carotid artery was conducted in 33 PA patients, 52 EH patients, and 33 normotensive individuals. 140 Haralick features and 10 wavelets were analyzed and utilized to train an XGBoost classifier. Additionally, the intima-media thickness (IMT) of the common carotid artery and left ventricular mass index (LVMi) were examined in 50 PHEO patients before and 5 years post- adrenalectomy and compared to 50 EH patients. In differentiating between PA and EH, we achieved a classification accuracy of 73 %, compared to the clinical gold...
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Analysis of echocardiographic findings in patients with primary and secondary hypertension using new sophisticated modalities
Kvasnička, Jan ; Holaj, Robert (advisor) ; Wohlfahrt, Peter (referee) ; Danzig, Vilém (referee)
6 Abstract Introduction: Heart damage in essential hypertension (EH) is one of the most serious consequences of high blood pressure. However, in the case of secondary hypertension, multiple pathophysiological effects may apply. For example, pheochromocytomas (PHEOs), which are tumors arising from the chromaffin cells of the adrenal medulla, have the ability to produce, metabolize, and secrete catecholamines. Overproduction of catecholamines leads to cardiac and other impairments by many mechanisms. The aim of our work was to verify this fact and at the same time to investigate whether global longitudinal strain (GLS), measured using speckle tracking echocardiography, can detect this damage earlier and also determine the adjustment of function after adrenalectomy. Methods: We analyzed 17 patients with PHEO and 18 patients with EH with the same hemodynamic parameters. Subsequently, we managed to increase the number of patients with PHEO to 24, and they were also examined 1 year after adrenalectomy. Results: Patients with PFEO did not differ in echocardiographic parameters including left ventricular ejection fraction compared to EH (0.69 ± 0.04 vs. 0.71 ± 0.05; NS), however, they had significantly lower GLS (−14.8 ± 1.5 vs. −17.8 ± 1.7; p < 0.001). One year after adrenalectomy, the GLS parameter improved...
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Study of Cancer Immunotherapy Mechanisms in Pancreatic Adenocarcinoma and Pheochromocytoma Murine Models
UHER, Ondřej
This dissertation examines the study of intratumoral cancer immunotherapy using a combination of phagocytosis-stimulating ligands and Toll-like receptor ligands (TLR) in murine pancreatic adenocarcinoma and pheochromocytoma murine models. In this study, we show that intratumoral application of the phagocytosis-stimulating ligand Mannan-BAM and three TLR ligands, referred to as MBT therapy, efficiently suppresses tumor growth in more than 83% of mice bearing murine melanoma. However, in aggressive pancreatic adenocarcinoma and pheochromocytoma murine models, such a combination is inefficient and must be combined with an agonistic anti-CD40 antibody, referred to as MBTA therapy, to achieve complete eradication of the tumor. We show that complex intratumoral MBTA therapy can systemically increase the recruitment of innate immune cells followed by activation of adaptive immune cells not only in treated tumors but also in distal non-treated lesions, resulting in the reduction of tumor growth and prolonged survival of treated mice. Taken together, these findings highlight the effect of MBTA therapy and the potential to optimize this therapeutic approach for future use in clinical trials as a treatment for metastatic cancers.
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The role adipose tissue in development of insulin resistance and other metabolic disorders in patients with pheochromocytoma
Klímová, Judita ; Petrák, Ondřej (advisor) ; Kříž, Jan (referee) ; Mlíková Seidlerová, Jitka (referee)
Pheochromocytoma and functional paraganglioma (PPGL) are rare neuroendocrine tumors characterized by catecholamines overproduction, which give a rise to disorders of glucose, lipid, and energy metabolism. The role of adipose tissue in these processes remains unclear. Our aim was to determine the gene expression profile in subcutaneous and visceral adipose tissue of patients with PPGL focusing on endocrine functions of adipose tissue, occurrence of brown (BAT) and beige adipose tissue (BeAT), all in connection with other measured metabolic and energy parameters and levels of circulating adipokines. We demonstrate signs of UCP1-dependent norepinephrine induced thermogenesis connected with overexpression of DIO2 in retroperitoneal VAT of PPGL and higher expression of key transcriptional factors of brown/beige adipogenesis, namely PPARGC1α, CEBPB and PRDM16. However, classic murine BAT or BeAT gene signature in VAT of PPGL was not detected. In subcutaneous adipose tissue (SAT) of PPGL we found signs of possible BeAT transformation, however without simultaneously undergoing UCP1-dependent thermogenesis. We also demonstrate that patients with PPGL have higher serum levels of FGF21 compared to healthy controls and these levels do not differ from obese patients. Furthermore, successful tumor removal...
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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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Possibilities of genetic testing in patients with pheochromocytoma and paraganglioma.
Turková, Hana ; Zelinka, Tomáš (advisor) ; Malík, Jan (referee) ; Fryšák, Zdeněk (referee)
1. Abstract Pheochromocytoma/ paraganglioma (FEO/PGL) may be developed on the basis of an inherited genetic mutation of different genes. They are associated with a high risk of developing of secondary hypertension, organ damage and metastatic disease that can be fatal. The aim was to focus on the possibility of genetic testing in patients with FEO/PGL, especially in patients with malignant tumors. The issue FEO/PGL, however, concerns not only the examination and assessment of risks arising therefrom, as well as other therapies and monitoring, including appropriate recommendations for clinical practice. We demonstrated a 20% incidence of cardiovascular (CV) complications before determining the final diagnosis of FEO/PGL, mainly arrhythmic, followed by complications of myocardial ischemia and accentuate atherosclerosis. Elevated levels of vitamin C and decreased levels of malondialdehyde (MDA) following the successful removal of the tumor demonstrated reduction of oxidative stress postoperatively. We found that early postoperative testing of levels of plasma metanephrines to confirm the success of surgical removal of FEO/PGL is already possible, since there was no significant correlation between plasma levels of metanephrines and postoperative examination interval. Distribution of frequency of metastatic...
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Molecular biological analysis of pheochromocytoma and paraganglioma.
Musil, Zdeněk ; Hirschfeldová, Kateřina (advisor) ; Zamrazilová, Hana (referee) ; Uhrová Mészárosová, Anna (referee)
This work summarizes the results of a research inquiring into relatively rare neuroendocrine tumors - pheochromocytomas and paragangliomas (PHEO/PGL) These tumors may arise on a hereditary genetic predisposition basis. On that account we primarily focused on a genetic examination of patients with PHEO/PGL. Methods for diagnostics of changes in SDHD, SDHB and RET genes were implemented. The number of examined genes has been (and is still being) extended. Currently we are investigating these genes: ATRX, BRAF, CDH1, CDKN2A, CDKN2B, FGFR1, FH, FHIT, GNAS, HIF2A (EPAS1), H-RAS, IDH1, IDH2, KIF1Bß, KMT2D, K-RAS, MAML3, MAX, MDH2, MET, NF1, NGFR, N-RAS, PHD2/EGLN1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TERT, TMEM 127, TP53 and VHL, using next generation sequencing. The number of variations of the above mentioned genes is different (23%) in Czech patients with PHEO/PGL in comparison with some foreign studies (27%, 40%). This may be caused by geographical influences or selection of patients. PHEO/PGL occur mainly (75%) in a benign form. A malignant form may be indicated by the presence of chromaffin tissue in locations where these tumors do not usually occur - liver, lungs, bones. In our study we focused on characteristics indicating the malignancy, for example, the lower age of patients with the first manifestation...
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Possibilities of genetic testing in patients with pheochromocytoma and paraganglioma.
Turková, Hana ; Zelinka, Tomáš (advisor) ; Malík, Jan (referee) ; Fryšák, Zdeněk (referee)
1. Abstract Pheochromocytoma/ paraganglioma (FEO/PGL) may be developed on the basis of an inherited genetic mutation of different genes. They are associated with a high risk of developing of secondary hypertension, organ damage and metastatic disease that can be fatal. The aim was to focus on the possibility of genetic testing in patients with FEO/PGL, especially in patients with malignant tumors. The issue FEO/PGL, however, concerns not only the examination and assessment of risks arising therefrom, as well as other therapies and monitoring, including appropriate recommendations for clinical practice. We demonstrated a 20% incidence of cardiovascular (CV) complications before determining the final diagnosis of FEO/PGL, mainly arrhythmic, followed by complications of myocardial ischemia and accentuate atherosclerosis. Elevated levels of vitamin C and decreased levels of malondialdehyde (MDA) following the successful removal of the tumor demonstrated reduction of oxidative stress postoperatively. We found that early postoperative testing of levels of plasma metanephrines to confirm the success of surgical removal of FEO/PGL is already possible, since there was no significant correlation between plasma levels of metanephrines and postoperative examination interval. Distribution of frequency of metastatic...
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Genetic changes in neuroectodermal tumors detected by molecular biological methods.
Vosecká, Tatiana ; Vícha, Aleš (advisor) ; Eckschlager, Tomáš (referee)
9 ABSTRACT Tatiana Labudová: Genetic changes in neuroectodermal tumours detected by molecular biological methods. Charles University in Prague, Faculty of Science, Department of Anthropology and Human Genetics Thesis, 75 pages,8 supplements, 2012 This thesis is concerned to neuroectodermal tumours that make a major group of infant tumour diseases. Genetic material gained from patients with neuroectodermal tumours was examined using comparative genomic hybridization (CGH) and interphasic fluorescence in situ hybridization (I-FISH). The aim of this Thesis is to prove chromosomal changes and to create the whole genetic profile. According to these profiles can be determined tumourgenetic cascade or specific genetic changes that lead to malignant tumours. In some cases (f.e. neuroblastoms) the genetic profile helps us to determine a subtype of disease and it's biological behaviour. Keywords: tumour diseases, neuroblastoma, CNS tumours, pheochromocytoma, Ewing's sarcoma, neuroectodermal tumour, comparative genomic hybridization, interphase fluorescence in situ hybridization
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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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