Oosterga, Margaretha

University of Groningen

   University of GroningenImportance of local renin-angiotensin systems and anti-ischemic effects of ACE-inhibitors inpatients with coronary artery disease.Oosterga, MargarethaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2000Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Oosterga, M. (2000). Importance of local renin-angiotensin systems and anti-ischemic effects of ACE-inhibitors in patients with coronary artery disease. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Part I of this thesis discusses the imporlance of the circulating and tissue localized renin-angiotensin system. Although tissue or local ACE seems quantitatively and qualitatrvelyfar more important than circulating or plasma ACE, elevated plasma ACE activify isshown to be a s igni f icant  and independent  predrctor  of  the development  of  le f tventricular dilation after myocardial rnfarction (Chapter I). The effects of manipulationof the renin-angiotensin system through ACE inhibitors, drugs reducing the conversionof angiotensin I to angiotensin II, was evaluated in the first parl of the QUO VADISstudy The effects of long-term orql trealment of ACE inhibitors on local ACEconcentrat ion,  i .e .  Iocal  angiotensin I l for rnat ion,  are descr ibed Treatment  wi th quinapr i lnot  only  resul ts  in  a s tat is t ica l ly  s igni f icant  reduct ion of  p lasma ACE. but  a lso in  astatistically significant reduction of local angiotensin II formation (()hapter 21.Treatment  wi th ACE inhib i tors reduce the r isk of  morta l i ty  and rnyocald ia l  in farct ionin patients with coronary artery disease. This rrsk reduction may be due to anti-ischemicef'fects of ACE inhibitors. [n parl I l , a review article describes various mechanisrns forthe anti-ischenric effects of ACE inhibitors (( 'hapter 3/. In the second paft of the QUOVADIS study,  the ef f icacy of  ACE inhib i tor  t reatment  on ischemia in  pat ients,  whounderwent coronary artery bypass grafting was evaluated. Chronic treatment withquinapril significantly reduces clinrcal ischemic events over the first year after coronaryaftery bypass surgery, providing evidence for the anti-ischemic properties of ACEinhibitors (( lhaprer 1).In parl IIl, the imporlance of alternative pathways are described, The formation ofangiotenstn Il does not seem to depend only on ACE, but also on other angiotensin IIfo l rnrng enzymes,  such as chymase.  Angiotenstn I l  receptor  b lockers prov ide theopportunity to study alternative pathways. The effects of ACE inhibit ion and angiotensinIl receptor blockade on angiotensin-mediated responses in the human vasculature werecornpared.  ln  an tn l l / ro  s tudy,  the ACE inhibr tor  captopr i l  incomplete ly  and theangiotensin I I -ATl  receptor  antagonist  i rbesar tan cornplete ly  b locks angiotensin I Ifnrmat ion.  lndeed,  these d i f - ferences r r r ight  be expla ined by non-ACE (chymase)angiotensin I I  format ion and seem especia l ly  i tnpor tant  dur ing an act ivated renin-angiotensin system (Ohapler 5)The importance of  in teract ions is  a lso descr ibed in pal t  l l l  ACE inhib i tors andaspirin are widely and concomitantly used in patients with coronary arlery disease. Bothdrugs exert their protective effect through a related-prostaglandin mediated pathway.Aspir in  does not  at tenuate the benef icra l  ef fegts of  ACE inhib i t ion af ter  acute rnyocardia linfarction, but independently reduces lefl ventricular dilation in patients after myocardialin f -arct ion.  Since re lat ive ly  low doses of  aspi r in  ef fect ive ly  b lock the format ion ofthromboxane Ar, without srgnificantly affecting prostaulandin formation, the negativeinteraction seems negligtble ((lhapter 6).Conclusions and future prospectivesIn patients with coronary artery disease, elevated plasma and tissue ACE, as a result ofactivation of the renin-angiotensin system. was proven to be harmful. Therefore,manipulation of the renin angiotensin system by reducing plasma and tissue ACE andangiotensin i l may be beneficial. ACE inhibitors, by reducing angiotensin Il activity,seem the drug of f irst choice. ln the QUO VADIS trial, quinapril signrficantly reducedplasma ACE and local angiotensin II. However, the ACE inhibitor captopril did notreduce local angiotensin l l forrnation, indicating a difference in tissue specificity betrveenvarious ACE inhibitors. Eventually, the reductron in local angiotensin II formation. byquinapril. resulted in the reduction in clinical ischemic events. The results of the HOPEstudy support our findings of anti-ischemic effects of ACE inhibitors. However. thepat ients in  QUO VADIS were compr ised of  avery specia lpost-CABG populat ion of  lowrisk patients, which was ercluded from the HOPE study. Recently, the IMAGINE trialhas been init iated. evaluating the effects of ACE rnhibitors when starled within 7 davsof coronary artery bypass surgery. During one year. a total of 2200 patients wil l receiveeither qurnapril or placebo. Since various ACE inhrbitors do not uniformlv reduce localangiotensin II, and may therefore have various anti-ischemic properlies, there is a needfor a comparing clinical trial between different ACE inhibitolsRecent reports indicate that angiotensin l l receptor blockers are more specific inreducing angiotensin I I  ln  contrast  to , {CE inhib i tors.  the angiotensin l l  receptorb lockers lack thei r  ef fect  on bradykin in breakdown. and consequent ly  n i t r ic  or ideproductron. Therefore. anlt-tschemrc'properltes may be a specrfic feature of ACEinhibitors. J' l.rere rs a strong need for a long-term study to evaluate possible beneflts onmorbid i ty  and morta l i ty  of  adding an angiotensin receptor  b locker  to ACE inhibr tortherapy. in pa/ien\.r u,ith curonut): arler.v disco.se. Recently. the results of RESOLVDindicated that in patients wrlh svmplotnutic heorl .failure. the combinaticln of anangiotensin I I receptor  b locker  and an ACE inhib i tor  was more benef ic ia l  for  prevent ingleft ventricular emodeling than either drug alone. We are expecting the results of thelong- term studies in  pat ients rv i th  symptomat ic  hear t  fa i lure,  the VaL-HeFT and theCHARM. in the next years.The safety of  the coadrnin is t rat ion of  ACE inhib i tors and aspi l in  s t i l l  remainsquest ioned ue to thei r  d ivergent  ef fects on the vascular  synthesis  of  vasodi la t ingprostaglandins. ln the HOPE trial, a negative interaction between aspirin and ramiprilwas found, the effects of ramipril being signifrcantly less marked in patients recervingaspirin. However, a post-hoc analysis of the CATS study revealed that aspirin did notattenuate the beneficial efl'ects of ACE inhibition after acute mvocaldial inlarction Ofcourse, the patient populations and analyses rvere not comparable, but concomitant user  1 aof ACE inhibrtors and asprrin seerned safe However, theoretically one could expect herewould be no interaction between angiotensin receptor blockers and aspinn and thereforetheir concomitant use would be safer.

Importance of local renin-angiotensin systems and anti-ischemic effects of ACE-inhibitors in patients with coronary artery disease.

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Importance of local renin-angiotensin systems and anti-ischemic effects of ACE-inhibitors in patients with coronary artery disease.

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