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SINKOPA MED NAPOROM PRI BOLNIKIH S STENOZO AORTNE ZAKLOPKE. REFLEKSNI MEHANIZEM?
Avtor: Marko Hazabent, Tomaž Jagric
Mentor: doc. dr. Matjaž Šinkovec
IZHODIŠCE: O mehanizmu sinkope med naporom pri aortni stenozi se razpravlja že vsaj pol stoletja. Podajali so razlicne razlage kot nemoc povecanja minutnega volumna, nenadna aritmija ali nenadna odpoved levega ventrikla. V zadnjih letih pa se vse bolj poudarja refleksni mehanizem sinkope pri aortni stenozi. NAMEN: Ena najpogostejših oblik sinkope je vazovagalna sinkopa, ki nastane po mnenju nekaterih avtorjev zaradi mocnih kontrakcij s krvjo slabo napolnjenega levega ventrikla. Kontrakcije dražijo ventrikularne mehanoreceptorje ali druge receptorje vezane na aferentno vagalno nitje. Sproži se kardioinhibitorni, vazodepresorni ali mešani odziv. Pogost sprožitveni dejavnik pri teh osebah je pokoncni telesni položaj - ortostaza. Refleksni mehanizem je pomemben tudi pri nekateh tipih kardialne sinkope (npr. obremenitvena sinkopa pri aortni stenozi). V literaturi omenjajo možne povezave med vazovagalno sinkopo in obremenitveno sinkopo pri aortni stenozi, vendar poskusov, ki bi to dokoncno potrdili še ni bilo. Zato smo bolnike z aortno stenozo (AS) in osebe z ortostatsko intoleranco vazovagalnega tipa (OI) testirali na cikloergometru (obremenitev je dražljaj sinkope pri aortni stenozi) in z nagibno mizo (ortostaza je dražljaj za vazovagalno sinkopo). HIPOTEZA: Sinkopa pri bolnikih z aortno stenozo je posledica istih refleksnih mehanizmov kot sinkopa pri osebah z ortostatsko intoleranco. METODE: Bolnike z AS (n=11) in osebe z OI (n=8) smo najprej obremenjevali na cikloergometru. Drugi test smo izvedli na nagibni mizi pri 9 bolnikih z AS in 7 osebah z OI. Ortostatski dražljaj smo potencirali s sublingvalno aplikacijo nitroglicerina (NTG). Pri obeh testih smo zapisovali EKG in merili srcno frekvenco (SF) ter arterijski tlak. Pozitivni rezultat testa je bila hipotenzija (<90/70 mm Hg) in/ali bradikardija (<60 min-1) s simptomi in znaki presinkope ali sinkope. Testiranim smo v mirovanju in ob pojavu simptomov odvzeli vzorec krvi za dolocitev koncentracij adrenalina (A), noradrenalina (NA), atrijskega natriureticnega peptida (ANP) in možganskega natriureticnega peptida (BNP). Za merjenje koncentracij srcnih peptidov sta bili uporabljeni metodi ELISA proANP(1-98) in EIA Nt-proBNP(8-29). Za dolocanje koncentracij A in NA je bila uporabljena RIA metoda. Variabilnost srcne frekvence smo analizirali s spektralno analizo pri 4 bolnikih z AS in 6 osebah z OI. Rezultate smo statisticno obdelali s Studentovim t-testom in Wilcoxonovim neparametricnim testom za odvisne in neodvisne vzorce. REZULTATI: Pozitivni rezultat pri testiranju z nagibno mizo smo dobili pri 5 od 9 bolnikov z AS in pri vseh osebah z OI. Pri vseh, razen pri eni osebi iz skupine z OI, je nastopila presinkopa po administraciji NTG. Vsi odzivi so bili vazodepresornega tipa. Bolniki z AS so imeli signifikantno višje vrednosti arterijskega tlaka med ortostazo (sistolicnega v 19 min: 129 26.9 proti 99 19.1 mm Hg in diastolicnega v 15. min: 72 14.3 proti 55 6.0 mm Hg) pred aplikacijo NTG in višjo SF med pripravo in pocitkom (73 14.9 proti 59 7.34 min-1 , p < 0.05). Pri bolnikih z AS je NTG povzrocil padec tlaka na nivo tlaka pri osebah z OI. Koncentracije A in NA so se povišale med ortostazo in presinkopo v obeh skupinah (p < 0.05). Pri bolnikih z AS je med presinkopo koncentracija A presegla normalne vrednosti (104 55.1 ng/L). Razlike med skupinama pa niso bile pomembne (p = NS). Bazalne vrednosti ANP (p < 0.05) in BNP (p = NS) so bile višje pri bolnikih z AS. Med presinkopo je le v skupini z AS koncentracija BNP narastla, koncentracija ANP pa padla. Koncentracija BNP je bila pomembno višja pri bolnikih z AS kot v skupini z OI (512 63.5 proti 399 89.9 pmol/L, p < 0.05). Med obremenitvijo na kolesu je bil porast arterijskega tlaka v skupini z AS vecji kot v skupini z OI (p < 0.05), SF pa enak (p = NS). Koncentracije A (p = NS) in NA (p < 0.05 v skupini z OI) so se med testom na podoben nacin povišale v obeh skupinah. Med testom sta vrednost ANP in BNP ostali na istem nivoju (p = NS). Moci nizkofrekvencnega dela spektra (LF) in kolicnika LF/HF sta v obeh skupinah narastli med presinkopo, moc visokofrekvencnega dela spektra (HF) pa je padla. Statisticno pomembnih razlik med skupinama nismo ugotovili. ZAKLJUCKI: Hipoteze nismo potrdili. Kljub temu, da je bil sam vazodepresorni odziv na ortostatski dražljaj enak v skupinah bolnikov z AS in osebah z OI, so bili sprožitveni dejavniki razlicni. Pri bolnikih z AS smo ugotovili pred sinkopo višji arterijski tlak, srcno frekvenco, koncentracijo kateholaminov in BNP. Pri osebah z OI je bil hemodinamski odziv manjši od pricakovanega, koncentracije srcnih natriureticnih peptidov pa nižje. Ob spremenjenih hemodinamskih razmerah pri bolnikih z AS, bi lahko aktivacija protektivnih mehanoreceptorjev levega ventrikla pripomogla k sprožitvi sinkope.
[Abstract / English version]
SINKOPA MED NAPOROM PRI BOLNIKIH S STENOZO AORTNE ZAKLOPKE. REFLEKSNI MEHANIZEM?
Author: Marko Hazabent, Tomaž Jagric
Mentor: doc. dr. Matjaž Šinkovec
BACKGROUND: The first discussions about possible mechanisms of exertional syncope in patients with aortic stenosis (AS) range back at least half a century. Since then many assumptions have been made about the cause of syncope, like the inability to increase the cardiac output, sudden arrhythmia or failure of the left ventricle. Many recent publications outline the importance of the reflex mechanism. AIM: Vasovagal syncope is most common type of sincope and is in most opinion caused by forceful contractions of the left ventricle. These stimulate ventricular mechanoreceptors or other receptors attached to afferent vagal fibers. Either cardioinhibitory, vasodepressor or mixed response is triggered. Upright position - orthostasis - is common triggering factor in these subjects. Reflex response also plays an important role in some types of cardial syncope (e.g. exertional syncope in patients with AS). The literature outlines possible connections between vasovagal syncope and exertional syncope of aortic stenosis, however, no attempts have been made to prove this connection experimentally. We tested patients with AS and subjects with orthostatic intolerance of vasovagal type (OI) on a cycloergometer (exertion is a stimulus for exertional syncope) and with a head-up tilt test (orthostasis is a stimulus for vasovagal syncope). HYPOTHESIS: Syncope in patients with aortic stenosis and syncope in subjects with orthostatic intolerance share the same reflex mechanisms. METHODS: Patients with AS (n=11) and subjects with OI (n=8) were first tested on a cycloergometer. Then 9 patients with AS and 7 subjects with OI were subjected to the head-up tilt test. Orthostatic stress was potentiated with sublingual administration of nitroglycerine (NTG). ECG, heart rate (HR) and arterial pressure were recorded during both of the tests. A positive test result was defined as hypotension (<90/70 mm Hg) and/or bradycardia (<60 min-1) accompanied by symptoms of impending loss of consciousness - presyncope or syncope. Two blood samples were taken for determination of concentrations of adrenaline (A), noradrenaline (NA), atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP): one during the supine rest and the other during the appearance of symptoms. The ELISA proANP(1-98) and EIA Nt-proBNP(8-29) methods were used for cardiac peptide concentration measurements. The RIA method was used for A and NA determinations. A spectral analysis of the heart rate variability was also performed in 4 patients with AS and 6 subject with OI. Data were submitted to Student t-test and Wilcoxon's nonparametric test for dependent or independent samples. RESULTS: Positive tilt test result was documented in 5 out of 9 patients with AS and in all subjects with OI. All, but one subject from control group, experienced presyncope only after NTG administration. Vasodepressor responses were documented in all cases. Patients with AS showed significantly higher arterial pressure during tilt (systolic in 19. min: 129 26.9 vs. 99 19.1 mm Hg and diastolic in 15. min: 72 14.3 vs. 55 6.0 mm Hg) before NTG administration, and HR during supine rest and recovery (73 14.9 vs. 59 7.34 min-1 , p < 0.05). In patients with aortic stenosis NTG induced drop of arterial pressure to the level of control subjects. A and NA concentrations increased during tilt and during presyncope in both groups (p < 0.05). In patients with AS, A concentration during presyncope exceeded normal range (104 55.1 ng/L). There were no significant differences between both groups (p = NS). Baseline ANP (p < 0.05) and BNP (p = NS) concentrations were higher in patients with AS. During presyncope, BNP concentration increased and ANP concentration decreased only in patients with AS. BNP concentration was significantly higher in AS group than OI group (512 63.5 vs. 399 89.9 pmol/L, p <0.05). During cycloergometry patients with AS showed significantly higher rise of arterial pressure (p < 0.05), and no difference in HR (p = NS). Concentrations of A (p = NS) and NA (p < 0.05 in OI group) showed similar increases in both groups. Values of ANP and BNP did not change during the test (p = NS). Powers of low frequency (LF) component and of ratio LF/HF increased during presyncope, and power of high frequency (HF) component decreased in both groups. We found no significant differences between both groups. CONCLUSIONS: We did not confirm our hypothesis. Although the vasodepressor response to orthostatic stress was the same, the triggering factors differed between groups of patients with AS and subjects with OI. Patients with AS showed higher arterial pressure, HR, catecholamine concentrations, and BNP during presincope. Subjects with OI showed subnormal hemodynamic response and lower values of cardiac natriuretic peptides. In the setting of altered hemodynamics in patients with AS activation of left ventricular protective mechanoreceptors could contribute to trigerring of syncope.