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Impatto emodinamico dopo impianto di stent in regione istmica dell'aorta in un modello animale
Full text linkObjectives:
The isthmic coarctation of the aorta accounts for 5-7% of all congenital heart diseases. Despite a full anatomic correction, almost 20-40% of the patients develop systemic hypertension later in their lives. Long-term follow-up studies demonstrate a reduced life expectancy for the patients born with an aortic coarctation because of increased risk for coronary artery disease and cerebral vascular incidents.
The pathogenesis of systemic hypertension following a coarctation repair seems to be related to the inappropriate response of the aortic baroceptors to the increased stiffness of the ascending aorta, which is present in every patient affected by an aortic coarctation.
The systemic hypertension, increasing the afterload, determines hypertrophy of the myocytes of the left ventricle. The reduced contractility of the hypertrophied myocytes is responsible for driving new hypertophy which eventually is responsible for heart failure.
Besides surgical therapies for relieving of the isthmic coarctation, nowadays the employment of endovascular stents have been successful in treating adolescents and adults affected by an aortic coarctation. Despite the extremely encouraging acute results of these endovascular techniques, no data are available regarding the long term results. Few data are available regarding the hemodynamic effect secondary to the presence of an stent and no data are available regarding the possible endotelial dysfunction secondary to the flow disturbance caused by the stent.
Aim of this animal study is to understand the hemodynamic impact of a bare metal stent in the isthmic region and how the disturbance of the normal laminar flow at the level of the stent might by responsible for dysfunction of the endothelium.
Materials and methods:
Eight female sheep of the same breed have been employed in this animal study. Between three to five months of age all the animals have been catheterized and in four of them a bare metal stent have been implanted in the aortic isthmus.
At the time of the first catheterization all the animals underwent a full echocardiographic examination collecting data regarding the systolic and diastolic functionality of the left ventrcle as well as data of its dimension and thickness.
All the animals have been followed every three months for a total of twelve months after the first catheterization. Every three months the blood pressure of each animals has been checked as well a new echocardiographic evaluation has been performed. At the time of the follow-up windows blood has been drawn and stored for subsequent analysis of the renin-angiotensin-aldosterone levels and kidney function.
At the end of the twelve months a new catheterization was performed collecting two different subsets of hemodynamic data: baseline and under simulated stress condition by continous infusion of Isopenaline titrated up to 10 mcgs/kg/min. After this catheterization each animals were sacrificed in order to collect tissue samples of the ascending and descending aorta and the heart for microscopic and molecular biology evaluations.
Results:
Since the beginning of the study in June 2008, a total of twelve animals have been catheterized and in eight of them a bare metal stent was successfully implanted.
Three of the eight sheep in which a stent was implanted didn't survived: one animal died during the procedure because of aortic dissection, and two animals died in the first week of follow-up because of sepsis. Another animal was excluded form the study because it developed severe aortic insufficiency duirng the follow-up.
Eight animals completed the twelve months of follow-up and were sacrificed.
At the end of the follow-up there were no statistical differences in the weigh and growth between the sham and the stented animals as no differences were recorded in terms of blood pressure. From an echocardiographic point of view the two groups didn't show any statistical difference in terms of LV hypertrophy and function.
The hystological analysis failed to show any difference in terms of hypertrophy and fibrosis of the left ventricle and in the architecture of the ascending and descending aorta between the sham and operated animals.
Since the two groups of animals didn't differ in any of the variables analyzed, we decided to not analyze the renin-angiotensin-aldosterone levels since we didn't expect any difference between the two groups.
The analysis of the expression of genes involved in the oxydative stress (MMP-9 and Caspase-3) failed to demonstrate any statistical significance between the two groups of animals.
Conclusions:
In this animal model the presence of a rigid metallic stent doesn't seem to impact the homeostatic regulation of the cardiovascular system and it isn't responsible for the development of systemic arterial hypertension in a growing animal.
Despite a trend of significance in the different expression of the MMP-9 in the aorta of the aninals with the stent compared to the sham ones, we cannot conlude the stent is responsible for the development of endothelial dysfunction.
The main limitations of this study are the small size of the sample, the limited time of follow-up and the different structure of the aorta of the sheep compared to the aorta of humans affected by coarctation of the aorta.
Our results might open new insights into the understanding of the development of the systemic hypertension after a coarctation repair. The increased stiffness of the aorta of these subjects might be secondary to the underline presence of endothelial dysfunction especially in those subjects corrected with implantation of a stent.
Further studies are needed to confirm our hypothesisObiettivi:
La coartazione istmica dell'aorta rappresenta il 5-7% di tutte le cardiopatie congenite. Nonostante un'efficace correzione anatomica, circa il 20-40% dei pazienti sviluppa un'ipertensione tardiva durante il follow-up. Studi di follow-up a lungo termine hanno dimostrato in questi malati una ridotta aspettanza di vita per un'aumentata incidenza di malattia coronarica e incidenti cerebro-vascolari.
L'eziopatogenesi dell'ipertensione tardiva sembra essere l'anomala risposta dei brocettori aortici conseguente all'aumentata rigidità dell'aorta ascendente presente sin dalla nascita in tutti i soggetti con coartazione aortica.
L'ipertensione arteriosa determinando un incremento dell'afterload del ventricolo sinistro causa ipertrofia dei miociti ventricolari che riducendo la loro capacità contrattile innesca un circolo vizioso che porta a scompenso cardiaco.
Al giorno d'oggi l'impianto di stent endovascolari ha sostituito le tradizionali tecniche chirurgiche nella correzione della coartazione aortica degli adolescenti e adulti. Nonostante gli eccellenti risultati immediati, non sono ancora disponibili dati certi del follow-up di questi pazienti a lungo termine. Sebbene sia stato dimostrato che la presenza di uno stent in regione istmica non sia in grado di alterare la compliance aortica, nulla si sa riguardo la possibile induzione di disfunzione endoteliale da alterazione del flusso ematico laminare a livello dell'interfaccia tra stent e aorta nativa.
Scopo del presente progetto di ricerca è studiare gli effetti emodinamici conseguenti all'impianto di uno stent sia in termini pressori che in termini di disfunzione endoteliale.
Materiali e Metodi:
Nel progetto sperimentale sono state impiegate otto pecore femmina di raazza Alpagota. A un'età compresa tra tre e cinque mesi tutti gli animali sono stati sottoposti a un cateterismo cardiaco e in quattro è stato impiantato uno stent in regione istmica. Tutti gli animali sono stati sottoposti a prima dello studio emodinamico a un'ecocardiografia completa per la determinazione della funzionalità sistolica e diastolica del ventricolo di sinistra così come per la determinazione dei volumi e spessori ventricolari.
A intervalli di tre mesi e per un totale di dodici mesi ciascun animale è stato sottoposto a regolari controlli ecocardiografici. A ciascun follow-up è stato poi prelevato un campione ematico per una successiva analisi dei livelli plasmatici della renina-angiotensina-aldosterone.
Al completamento dei dodici mesi di follow-up è stato ripetuto un nuovo studio emodinamico per la determinazione invasiva della pressione arteriosa di base e dopo stress test mediante infusione di dobutamina sino al dosagggio massimo di 10 mcg/kg/min. Terminato il cateterismo cardiaco ciascun animale è stato sacrificato e sottoposto a studio autoptico per il prelevamento di campioni tissutali dell'aorta ascendente e discendente e del miocardio del ventricolo di sinistra e dei reni per studi istologici e di biologia molecolare.
Risultati:
Dall'inizio dello studio nel giugno del 2008, un totale di dodici animali sono stati sottoposti a studio emodinamico e in otto è stato impiantato un stent metallic in regione istmica.
Delle otto pecore in cui uno stent è stato impiantato, una è deceduta in sede operatoria per dissezione aortica, due sono deceduti nella prima settimane di follow-up per sepsi, una è stata esclusa dallo studio per lo sviluppo di un sevra insufficienza aortica durante il follow-up.
Otto animali hanno completato I dodici mesi di follow-up e sono stati sacrificati.
I due gruppi di animali non hanno mostrato differenza statisticamente signnificative né in termini del comportamento pressorio né in termini di funzionalità e volumetrica del ventricolo di sinistra. A livello istologico non abbiamo riscontrato differenze in termini di fibrosi e ipertrofia del ventricolo di sinistra e nell'architettura della parete aortica.
I livelli plasmatici degli ormoni renina-angiotensina-aldosterone non sono stati determinati vista la mancanza di differenza statisticamente significative delle variabili esplorate.
L'analisi dell'espressione genica dei geni attivati in condizioni di stress ossidativo (MMP-9 e Caspasi-3) non ha evidenziato differenze nei due gruppi.
Conclusioni:
I risultati di questo progetto sperimentale sembrerebbero suggerire l'ininfluenza della presenza di uno stent metallico sull'omeostasi pressoria. Nonostante vi siano delle differenze nei livelli di espressività delle MMP-9 a livello dell'aorta degli animali portatori di stent, queste differenze, verosimilmente a causa della bassa numerosità del campione oggetto di studio, non si sono dimostrate statisticamente significatieve.
I limiti maggiori del nostro progetto sperimentale risiedono nella bassa numerosità del campione di studio, nel periodo limitato di follow-up e nelle differenze strutturali esistenti tra l'aorta degli ovini e l'aorta dei soggetti affetti da coartazione aortica.
L'irrigidimento aortico caratteristico dei soggetti nati con coartazione aortica potrebbe essere secondario alla presenza di una disfunzione endoteliale e la presenza di uno stent in aorta potrebbe essere motivo di aggravamento di tale alterazione.
Ulteriori studi saranno necessari al fine di valutare l'appropriatezza delle nostre ipotes
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No full textOBJECTIVES:
We report our 8-year experience with surgery for congenital heart disease in adults in a medium-volume surgical center.
METHODS:
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RESULTS:
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CONCLUSION:
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