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Anesthetic Preconditioning in Normal and Hypertrophic Porcine Myocardium

Jens K. Rolighed Larsen  


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Accepted by: Health Sciences Aarhus
Defended on: October 24, 2008
Official opponents: Else K. Tønnesen , Niels Gadsbøll , Niels Vidiendal Olsen
Tutors: John Michael Hasenkam , Erik Sloth

Published in the PhD Database: October 1, 2008


English abstract
The effect of volatile anesthetics on cardiomyocyte injury during ischemia and reperfusion is not yet fully understood. Though the efficacy of sevoflurane upon reducing myocardial infarction during the ischemia-reperfusion process is well-validated in some animal models, clinical studies are partially inconsistent with this, and the cardioprotective effect is yet to be translated into an equivocal improvement in patient outcome.
We, therefore, used an intact porcine closed-chest animal model with anatomic and physiological similarities to man to investigate sevoflurane volatile anesthetic cardioprotection during ischemia and reperfusion. In order to form a comparative base, we initially studied the efficacy of ischemic preconditioning upon histologic myocardial infarct size and simultaneously investigated the effects of sevoflurane administered pre-ischemically, which resulted in a trend towards infarct size reduction, in comparison to effective ischemic preconditioning. Global cardiac function was estimated with tissue-Doppler echocardiography and was unrelated to sevoflurane administration or infarct size.
Thus, unable to prove the existence of a trigger mechanism for sevoflurane preconditioning, we evaluated infarct size mitigation by continuous pre-, per- and post-ischemic sevoflurane administration. Sevoflurane inhalation diminished myocardial infarct size by 60-68%, with or without concomitant pentobarbital anesthetic infusion.
Finally, the pathologic heart condition known as left ventricular hypertrophy (LVH), commonly encountered in cardiac surgery patients, was investigated for its influence on sevoflurane cardioprotection in the porcine model. A model of LVH already established within our department was used. A cohort of aortic banded animals, which subsequently developed supravalvular aortic stenosis and LV pressure overload, with ensuing development of LV hypertrophy was used. Animals were since allocated to ischemia-reperfusion protocols and this showed that LVH sevoflurane cardioprotection was largely unaffected, in addition to LVH paradoxical improved tolerance to ischemia in young animals.
In conclusion, this dissertation supports previous experimental results from volatile anesthetic cardioprotection and specifies timing and dosages related to sevoflurane administration in an intact large animal model recognized for its comparability to normal human ischemia pathophysiology. Moreover, sevoflurane cardioprotective efficacy was unchanged in a model of cardiac LVH pathology, offering a possible explanation for diminished clinical capacity for cardioprotection in a typical cardiac surgery cohort.



Danish abstract
Læge Jens Kjærgaard Rolighed Larsen:

Anesthetic Preconditioning in Normal and Hypertrophic Porcine Myocardium

Ph.D.-afhandling


Afhandlingen er udført på Klinisk Institut under min ansættelse som klinisk assistent, Skejby 2005-2008.
Afhandlingen er baseret på følgende tre arbejder:

I. Pre-occlusion ischaemia, not sevoflurane, successfully preconditions the myocardium against further damage in porcine in vivo hearts.
Larsen JR, Aagaard SR, Hasenkam JM, Sloth E.
Acta Anaesth Scand 2007; 51: 402-409.

I I. Sevoflurane Improves Myocardial Ischaemic Tolerance in a Closed-Chest Porcine Model.
Larsen JR, Aagaard SR, Lie RH, Sloth E, Hasenkam JM.
Acta Anaesth Scand 2008; accepted for publ.

I I I. Left ventricular hypertrophy: sevoflurane cardioprotection retained and
ischaemic tolerance improved.
Larsen JR, Smerup MH, Hasenkam JM, Christensen SD, Sivesgaard K, Torp P, Sloth E.
British J Anaesthesia 2008; submitted.

Formål: Halogenerede gasanæstetikas effekt på myokardieceller under iskæmi og reperfusion er endnu ikke fuldt klarlagt, men eksperimentelle studier tyder på, at endogene cellulære forsvarsproteiner aktiveres på linje med ¿klassisk¿ iskæmisk prækonditionering. Eksempelvis kan sevoflurane markant reducere størrelsen i myokardieinfarkt (MI) efter iskæmi-reperfusion i eksperimentelle in vitro og in vivo studier. Kliniske undersøgelser er dog inkonsistente med dette, og der savnes endnu et samlet entydigt bevis på forbedret klinisk resultat som følge af denne effekt.
Afhandlingen havde til formål at belyse om sevoflurane kunne reducere graden af irreversible iskæmiske myokardieskader i forbindelse med langvarig koronarokklusion og reperfusion. Ved anvendelsen af en intakt dyremodel i gris, som anses for at være i besiddelse af de bedste komparative hjerteanatomiske og -fysiologiske egenskaber i forhold til mennesket, udnyttedes disse egenskaber til at vurdere effekten af sevoflurane på størrelsen af MI efter koronarokklusion- i aktuelle tilfælde forårsaget af ballon-kateter aflukning.
Art: Eksperimentelle studier i en grisemodel.
Resultater: I første delstudie fandtes signifikant nedsættelse af MI ved iskæmisk prækonditionering (2 x 5 min), hvorimod en ikke-signifikant nedsættelse af MI på 30 % fandtes som følge af præ-iskæmisk sevoflurane tilførsel. I delstudie II fandtes hhv. 68 og 60 % reduktion i MI som resultat af kontinuerlig præ-, per- og post-iskæmisk sevoflurane tilførsel alene, eller i kombination med kontrolanæstetikum (pentobarbital). I Delstudie III fandtes, i dyr med venstre ventrikelhypertrofi, nedsættelse af MI-størrelsen alene på baggrund af hypertrofien, samt effekt af sevoflurane.
Hermed indhentedes ny viden til støtte for kliniske rekommandationer om den hjertebeskyttende effekt af sevoflurane under iskæmi, som kan forekomme under bypasskirurgi og ballonkateter operationer.


Forf.s adresse: Klinisk Institut, Århus Universitetshospital, Skejby, Brendstrupgaardsvej 100, DK-8200 Århus N.
E-mail: jens.rolighed@ki.au.dk
Forsvaret finder sted den 24. oktober 2008, kl.14.00, Disputatsauditoriet, bygn. 1231, Århus Universitet.
Bedømmere: Else Kirstine Tønnesen (fmd), Niels Gadsbøll og Niels Vidiendal Olsen.
Vejledere: John Michael Hasenkam og Erik Sloth.