Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.
- MeSH
- aneurysma hrudní aorty genetika patofyziologie MeSH
- aorta metabolismus MeSH
- arterie metabolismus MeSH
- disekce aorty genetika patofyziologie MeSH
- dospělí MeSH
- genetická predispozice k nemoci genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- lysyloxidasa genetika metabolismus MeSH
- mutace genetika MeSH
- nemoci pojiva genetika MeSH
- pojivová tkáň metabolismus MeSH
- rodokmen MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
The assessment and monitoring of the tissue perfusion is extremely important in critical conditions involving circulatory shock. There is a wide range of established methods for the assessment of cardiac output as a surrogate of oxygen delivery to the peripheral tissues. However, the evaluation of whether particular oxygen delivery is sufficient to ensure cellular metabolic demands is more challenging. In recent years, specific biochemical parameters have been described to indicate the status between tissue oxygen demands and supply. In this review, the authors summarize the application of some of these biochemical markers, including mixed venous oxygen saturation (SvO2), lactate, central venous-arterial carbon dioxide difference (PCO2 gap), and PCO2 gap/central arterial-to-venous oxygen difference (Ca-vO2) for hemodynamic assessment of tissue perfusion. The thorough monitoring of the adequacy of tissue perfusion and oxygen supply in critical conditions is essential for the selection of the most appropriate therapeutic strategy and it is associated with improved clinical outcomes.
- MeSH
- arterie metabolismus MeSH
- biologické markery metabolismus MeSH
- blízká infračervená spektroskopie MeSH
- glukosa metabolismus MeSH
- hemodynamika MeSH
- hypoxie MeSH
- kyselina mléčná MeSH
- kyslík metabolismus MeSH
- lidé MeSH
- mikrocirkulace * MeSH
- monitorování fyziologických funkcí metody MeSH
- oxid uhličitý MeSH
- perfuze MeSH
- prognóza MeSH
- spotřeba kyslíku MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Thrombospondins (TSPs) are matricellular glycoproteins expressed in response to vascular injury. TSP-1 and TSP-2 are promotors of arterial remodeling while TSP-5 is believed to be protective. The current study assessed the differential effect of TSPs on protein expression in vascular smooth muscle cells (VSMCs). We hypothesized that TSP-1, TSP-2 and TSP-5 would regulate VSMC proteins involved in arterial remodeling. Human VSMCs were exposed to TSP-1, -2, -5 or serum free media (24 hours). Cell lysates were used to assess the targets TSP-1, TSP-2, TSP-5 and CD44), while the culture media was used to detect TGF-ß1, PDGF-BB, ANGPTL-4 and IL-8. Statistical analysis was performed by t-test and p< 0.05 was considered significant. All TSPs increased their own expression and TSP-5 increased TSP-2. TSP-1 and TSP-2 increased production of ANGPTL-4 and PDGF-BB, while TSP-5 only increased ANGPTL-4. TSP-1 increased exclusively TGF-ß1 and CD44 production. TSP-2 increased TSP-1 expression. All TSPs decreased IL-8. The findings suggest that TSP-1 and TSP-2 may promote vascular remodeling, in part, by increasing ANGPTL-4, PDGF-BB and their own expression. TSP-5 did not upregulate the inflammatory mediators TSP-1, PDGF-BB or TGF-ß1, but upregulated its own expression, which could be a protective mechanism against the response to vascular injury.
- MeSH
- arterie metabolismus MeSH
- chrupavkový oligomerní matrixový protein biosyntéza MeSH
- kultivované buňky MeSH
- lidé MeSH
- myocyty hladké svaloviny metabolismus MeSH
- remodelace cév fyziologie MeSH
- svaly hladké cévní metabolismus MeSH
- thrombospondin 1 biosyntéza MeSH
- thrombospondiny biosyntéza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The primary purpose of this study was to assess the response of autonomic cardiac activity and changes in the arterial oxygen saturation (SpO2) during normobaric hypoxia and subsequent recovery. Heart rate variability (HRV) and SpO2 were monitored in a supine position during hypoxia (FiO2=9.6%) for 10min, and normoxic recovery in 29 subjects. Spectral analysis of HRV quantified the autonomic cardiac activity by means of low frequency (LF) (0.05-0.15Hz) and high frequency (HF) (0.15-0.50Hz) power transformed by natural logarithm (Ln). Based on the SpO2 response to hypoxia, the subjects were divided into Resistant (RG, SpO2=80.8±7.0%) or Sensitive (SG, SpO2=67.2±2.9%) group. The SpO2 and vagal activity (LnHF) significantly decreased during hypoxia in both groups. A withdrawal in vagal activity was significantly greater in SG compared to RG. Moreover, only in SG, a relative increase in sympathetic modulation (Ln LF/HF) during hypoxia occurred. Correlations (r=-0.461, and r=0.595, both P<0.05) between ΔSpO2 (delta) and ΔLn LF/HF, and ΔLnHF were found. Based on results, it seems that SpO2 level could be an important factor that influences the autonomic cardiac response in hypoxia.
- MeSH
- arterie metabolismus MeSH
- dospělí MeSH
- hypoxie patofyziologie MeSH
- kyslík krev MeSH
- lidé MeSH
- nervus vagus patofyziologie MeSH
- srdeční frekvence fyziologie MeSH
- sympatický nervový systém patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Treatment with pertussis toxin (PTX) which eliminates the activity of G(i) proteins effectively reduces blood pressure (BP) and vascular resistance in spontaneously hypertensive rats (SHR). In this study we have compared the functional characteristics of isolated arteries from SHR with and without PTX-treatment (10 microg/kg i.v., 48 h before the experiment). Rings of thoracic aorta, superior mesenteric artery and main pulmonary artery were studied under isometric conditions to measure the reactivity of these vessels to receptor agonists and to transmural electrical stimuli. We have found that the treatment of SHR with PTX had no effect on endothelium-dependent relaxation of thoracic aorta induced by acetylcholine. In PTX-treated SHR, the maximum contraction of mesenteric artery to exogenous noradrenaline was reduced and the dose-response curve to cumulative concentration of noradrenaline was shifted to the right. Similarly, a reduction in the magnitude of neurogenic contractions elicited by electrical stimulation of perivascular nerves was observed in the mesenteric artery from PTX-treated SHR. PTX treatment of SHR also abolished the potentiating effect of angiotensin II on neurogenic contractions of the main pulmonary artery. These results indicate that PTX treatment markedly diminishes the effectiveness of adrenergic stimuli in vasculature of SHR. This could importantly affect BP regulation in genetic hypertension.
- MeSH
- acetylcholin metabolismus MeSH
- adrenergní látky metabolismus MeSH
- angiotensin II metabolismus MeSH
- aorta thoracica metabolismus účinky léků MeSH
- arteria mesenterica superior metabolismus účinky léků MeSH
- arteria pulmonalis metabolismus účinky léků MeSH
- arterie metabolismus účinky léků MeSH
- cévní endotel metabolismus účinky léků MeSH
- elektrická stimulace MeSH
- hypertenze farmakoterapie metabolismus MeSH
- inhibitory enzymů farmakologie MeSH
- krevní tlak genetika účinky záření MeSH
- krysa rodu rattus MeSH
- noradrenalin metabolismus MeSH
- pertusový toxin farmakologie MeSH
- potkani inbrední SHR MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go antagonisté a inhibitory metabolismus MeSH
- signální transdukce fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- arterie metabolismus MeSH
- bakteriemie patologie MeSH
- dinoprost analogy a deriváty metabolismus MeSH
- finanční podpora výzkumu jako téma MeSH
- játra metabolismus MeSH
- lysin analogy a deriváty farmakologie MeSH
- prasata MeSH
- Pseudomonas aeruginosa metabolismus MeSH
- sepse MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- acetylcholinesterasa metabolismus MeSH
- adrenergní vlákna enzymologie patologie MeSH
- arterie inervace metabolismus MeSH
- formaldehyd metabolismus MeSH
- katecholaminy metabolismus MeSH
- kočky MeSH
- králíci MeSH
- krční mandle inervace krevní zásobení metabolismus MeSH
- serotonin metabolismus MeSH
- zvířata MeSH
- Check Tag
- kočky MeSH
- králíci MeSH
- zvířata MeSH
- Klíčová slova
- BATIMASTAT (BRIT.BIOTECH.PHARM.LTD.,OXFORD,UK),
- MeSH
- arterie metabolismus účinky léků MeSH
- hypoxie komplikace MeSH
- kolagenasy antagonisté a inhibitory MeSH
- krysa rodu rattus MeSH
- plicní hypertenze etiologie farmakoterapie metabolismus MeSH
- srdeční komory radiografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- arterie metabolismus účinky léků MeSH
- guanylátcyklasa antagonisté a inhibitory fyziologie MeSH
- krysa rodu rattus MeSH
- oxid dusnatý farmakologie MeSH
- plíce metabolismus MeSH
- plicní hypertenze MeSH
- proteinkinasy závislé na cyklickém GMP antagonisté a inhibitory fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
V současném pojetí je ateroskleróza proces s mnoha charakteristikami chronického fibroproliferatativního, především chemicky indukovaného zánětu s aspekty střádavého procesu. Primárním místem poškození tepen jsou endotelie. K jejich poškození dochází zejména pod vlivem LDL, ale i dalších, především chemických etiologických činitelů, jako jsou například některé složky tabákového kouře, homocystein a hypoxic. K endoteliálnímu postižení přispívá i hypertenze. V endoteliích dochází k mírné oxidaci LDL. Pod vlivem mírně oxidovaných LDL endotelie produkují řadu látek, především z oblasti adhezivních molekul, chemoatraktantů a růstových faktorů. Díky působení těchto látek jsou do I faktorů transformují v makrofágy. Do makrofágů vstupují přes scavengerové receptory mírně oxidované LDL, které jsou v nich definitivně oxidovány, přičemž jsou makrofágy transformovány na pěnové buňky. Pěnové buňky již nejsou schopny migrace, produkují však i nadále cytokiny a růstové faktory, které se podílejí na chaotickém růstu svaloviny médie tepny. Některé svalové buňky migrují do subintimálního prostoru. Fibroblasty pod vlivem růstových faktorů a cytokinů produkuji ve zvýšené míře kolagen. Po zániku pěnových buněk dochází k uvolnění tuhých krystalů cholesterolu, které jsou deponoány extracelulámě v cévní stěně. Na periferii ateromatózní leze se nacházejí i plazmocyty a lymfocyty. Celý ateromový plát je kryt tenkým fibrózním krytem. Enzymy na povrchu pěnových buněk a makrofágů, metaloproteinázy, se zřejmě významně podílejí na fisuraci a rupture tohoto krytu. Ruptúra plátu je významnou determinantou jeho instability, progrese, při které se ateromový plát prolabuje do lumina cévy, dochází ke konečné trombotizaci a projevům klinicky významné ischemické choroby srdeční. V poslední době přibývá důkazů o možných vlivech prodčlané cytomegalové nebo chlamydiové infekce na nestabilitu ateromového plátu. Ateroskleróza má tedy charakter chemicky indukovaného zánětiivého proliferativního procesu. Toto poznání má řadu potenciálních implikací pro prevenci i terapii.
According to the contemporary concept atherosclerosis is a process with many characteristics of a chronic proliferative, mainly chemicaly induced inflammation with aspects of a storage process. The primary site of vascular damage is the endothelium. Its damage occurs in particular due to LDL as well as other, in particular chemical etiological factors such as e.g. some constituents of tobacco smoke, homocysteine and hypoxia. Endothelial damage is promoted also by hypertension. In the endothelium mild oxidation of LDL takes place. Under the influence of slightly oxidized LDL the endothelium produces a number of substances, in particular adhesive molecules, chemoattractants and growth factors. Due to the action of these substances into the subintimal area of the artery monocytes are attracted which under the influence of various growth and maturation factors are transformed into macrophages. Into the latter enter via scavenger receptors slightly oxidized LDL which then are definitely oxidized, whereby the macrophages are transformed into foam cells. Foam cells are uncapable of migration, they continue to produce however cytokines and growth factors which participate in the chaotic growth of the musculature of the arterial media. Some muscle cells migrate into the subintimal space. Fibroblasts under the influence of growth factors and cytokines produce increased amounts of collagen. After the disintegration of foam cells solid cholesterol crystals are released which are- deposted extracellularly in the vascular wall. On the periphery of the atheromatpous lesion are plasmocytes and lymphocytes. The entire atheromatous plaque in covered by a thin fibrous cap. Enzymes on the surface of foam cells and macrophages, metalloproteinases, participate apparently in ä significant way in Assuring and rupture of this cover. Rupture of the plaque is an important determinant of its instability, progression during which the atheromatous plaque prolapses into the vascular lumen and final thrombotization develops and manifestations of clinically significant ischaemic heart x infection in the case-history on the instability of the atheromatous plaque. Atherosclerosis thus has the character of a chemically induced inflammatory proliferative process. This finding has a number of potential implications for prevention and treatment.
