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KALP İSKEMİSİNDE YENİ BOYUTLAR
Doç.Dr.Tayfun Güler
24.10.2002
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KALP İSKEMİSİNDE YENİ = BOYUTLAR
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Miyokard iskemi= si
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Reperfüzyon has= arı
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Stunning <= /span>
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•İskemik önhazırlama
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Hibernasyon = 3;
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Apopitozis
Miyoka= rd iskemisi:
   Gelişen olaylar
   Geri dönebilir iskemi hasarı
   Geri dönüşsüz iskemi hasarı
Miyoka= rd nekrozunun önlenmesi:
   Reperfüzyon
   İskemik hasar gelişme hızının azaltıl= ması
Reperf= üzyon hasarı
   Reperfüzyon hasarının önlenmesi
   Reperfüzyon hasarının tedavisi=
   Reperfüzyon tipleri
Stunni= ng
İskemik önhazırlama
Hibern= asyon
Apopit= ozis

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MİYOKARD İSKEMİSİ
Enfarktüs
Derlenme
<= ![if !ppt]>
Reperfüzyon
<= ![if !ppt]>
Uzun süreli
 = iskemi
Bölgesel &#= 13;
duvar hareketi
anormalliği
Koroner = ;
iskemi
Miyoka= rd iskemisi, erken reperfüzyon ile kesintiye uğramadıkça progressif olarak ilerleyen ve sonuçta hücre ölümü ve doku nekrozuna kadar gidebilen bir hücresel zedelenmeye yol açar.
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MİYOKARD İSKEMİSİ
Geri dönebilir
hasar
•Subendo- =
•kardiyal = ;
•nekroz=
•Nekrozun yayılması (midmiyokard, subepikard)
•Transmural &#= 13;
•enfarktüs
    Risk bölges= i
Nekroz
20 dk   =   
40 dk
3 st
> 3-6 st
Geri dönüşsüz hasar
= Sol
= ventrikül
Koroner
oklüzyon
•İskemi
•Canlı doku
•
Kısa s= üreli miyokard iskemisi miyositler tarafından genellikle iyi tolere edilir.Hücre ölümü olmaz ancak miyositlerde hasar oluşur.
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Geri dönebilir
hasar
    Risk bölges= i
Nekroz
20 dk
40 dk   =    
3 st
> 3-6 st
= Sol
= ventrikül
Geri dönüşsüz hasar
Koroner
oklüzyon
•Subendokardiyal= nekroz
MİYOKARD İSKEMİSİ
•Buna karşılık iskemi süresi uzadıkça geridönebilir karakterde zedelenmiş hücre sayısı, reperfüzyon ile kurtarılabilecek doku miktarı ve normal kontraktil işlevin geri dönüş şan= sı azalır.
•İskemi süresinin 20 dk.nın üzerine = çıkması ile miyokardın iskemiye en duyarlı bölgesi olan endokardta nekroz başlar.=
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Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="Windows-1254" KALP İSKEMİSİNDE YENİ BOYUTLAR
Geri dönebilir
hasar
    Risk bölges= i
Nekroz
20 dk
40 dk
  3 st     
> 3-6 st
= Sol
= ventrikül
Geri dönüşsüz hasar
Koroner
oklüzyon
•Nekrozun yayılması (midmiyokard, subepikard)=
Mİ= YOKARD İSKEMİSİ
Miyoka= rd iskemisinin uzaması ile birlikte miyokard duvarında gelişmeye başlayan nekroz, subendokardiyal alana dek ilerler.

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Geri dönebilir
hasar
    Risk bölges= i
Nekroz
20 dk
40 dk
3 st
> 3-6 st
Geri dönüşsüz hasar
= Sol
= ventrikül
Koroner
oklüzyon
•Transmural
•enfarktüs
Mİ= YOKARD İSKEMİSİ
3 saat= i aşan iskemilerde ise artık transmural tipte bir enfarktüs tablosu oturur.
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file:///C:/2AC9C632/tark2002_dosyalar/slide0010.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="Windows-1254" KALP İSKEMİSİNDE YENİ BOYUTLAR
FİZYOLOJİK VE
METABOLİK DEĞİŞİKLİKLER (I)
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Anaerobik metabolizma
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Kontraktilitede= azalma ve durma
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•EKG değişiklikl= eri
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•ATP ¯, ADP ­
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Kreatin fosfat tükenmesi
•Laktat ve H+ bi= rikimi, pH’da azalma
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Hücre ödemi
Mİ= YOKARD İSKEMİSİ
Büyük = bir hayvan kalbinde koroner kan akımının birden kesilmesi, saniyeler içinde bir takım fizyolojik ve metabolik değişikliklerin gelişmesine neden olur.  Dokuda oksihemoglobin ve oksimiyoglob= in tükendiği an enerji metabolizması aerobik ya da mitokondriyal metabolizma= dan anaerobik metabolizmaya kayar (8 sn içinde).
Miyoka= rd her sistolde kısalma yerine ancak gerilir. Daha sonra iskemik miyokardın kontraktilitesi azalır ve ardından durur.
Membran potansiyeli azalır, EKG değişiklikleri gözlenmeye başlar.
•Miyositlerin enerji gereksinimi ana= erobik glikoliz ile ve yüksek enerjili fosfat (YEF) depolarından sağlanan enerji miktarını aştığından  doku ATP dü= zeyi azalır,  ADP birikmeye başlar.
•YEF’lar için önemli bir enerji kayn= ağı olan kreatin fosfat hızla azalır. İskeminin başlamasından 30 sn sonra %90 oran= ında azalmıştır. ATP’deki azalma ise nispeten daha yavaş olur.<= br>
•Laktat ve H+ birikimi sürer. İskemi= nin başlamasından 10 dk sonra intrasellüler pH, 5.8-6.0 ‘a düşmüş; aktif partiküller, laktat, inorganik fosfat, kreatin vb nedeniyle intrasellüler osmolarite anlamlı ölçüde artmıştır. Bu osmotik yük, elektron mikroskopis= inde görülebilecek kadar hücre ödemine neden olur.


------=_NextPart_01C2E70A.04E4FC00 Content-Location: file:///C:/2AC9C632/tark2002_dosyalar/slide0010_image059.gif Content-Transfer-Encoding: base64 Content-Type: image/gif R0lGODlhgQAWAHcAMSH+GlNvZnR3YXJlOiBNaWNyb3NvZnQgT2ZmaWNlACH5BAEAAAAALAAAAAB/ ABQAhAAAAB0dVxkZThgYSRgYShsbUR4eWikpfCUlcCEhYyIiZiYmdDIylzExlC8vjy0thyoqgC4u ijAwkTIylTMzmAECAwECAwECAwECAwECAwECAwECAwECAwECAwECAwECAwX/ICOOZGmeaKqubOu+ ZyPPdG3feK7vfO//N4dwSCwaj8ikcslsOp/Hh3RKrVqv2Kx2y+16v9eDeEwum8/otHrNbrvfZ4R8 Tq/b7/i8fs/v+/93CYKDhIWGh4iJiouMjY6PhwGSk5SVlpeYmZqbnJ2en5cCoqOkpaanqKmqq6yt rq+nA7KztLW2t7i5uru8vb6/twTCw8TFxsfIycrLzM3Oz8cF0tPU1dbX2Nna29zd3t/XBuLj5OXm 5+jp6uvs7e7v5wry8/T19vf4+fr7/P3+//cWCBxIsKDBgwgTKlzIsKHDhwchSJxIsaLFixgzatzI saPHjxcjiBxJsqTJkyhTQKpcybKly5cnJcicSbOmzZs4c+rcybOnz583JwgdSrSo0aNIkypdyrSp 06dHKUidSrWq1atYs2rdyrWr169XQwAAOw== ------=_NextPart_01C2E70A.04E4FC00 Content-Location: file:///C:/2AC9C632/tark2002_dosyalar/slide0012.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="Windows-1254" KALP İSKEMİSİNDE YENİ BOYUTLAR
İSKEMİK ZARARIN HIZINI = ETKİLEYEN FAKTÖRLER
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Kolateral akım =
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Yandaş hastalık= lar
•Kalp hızı, meta= bolik hız ve doku sıcaklığı,
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Nütrisyonel ve = hormonal durum,
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Kardiyoaktif il= açlar
<= span class=3DBB style=3D'position:absolute;left:-3.88%'>•Daha önceki isk= emik ve adaptif olaylar,
•Yaş, cinsiyet ve iskemik dokunun türü
<= span style=3D'visibility:hidden'>•
İskemi= k kalpte doku zedelenmesinin hızını etkileyen, çok sayıda ve birbirinden de etkile= nen faktör bulunmaktadır.
Bu fak= törlerin en önemlileri arasında
(1) re= sidüel koroner veya nonkoroner kolateral akımın varlığı ve miktarı,
(2) hi= pertrofi, diyabet ya da hipertansiyon gibi iskemi nedeni olabilecek yandaş hastalıkların varlığı,
(3) ka= lp hızı, metabolik hız ve doku sıcaklığı,
(4) nü= trisyonel ve hormonal durum,
(5) ka= rdiyoaktif ilaçların varlığı,
(6) da= ha önceki iskemik ve adaptif olaylar,
(7) ya= ş, cinsiyet ve iskemik dokunun türü sayılabilir.
Bu fak= törlerin değişik kombinasyonları nedeniyle iskemik dokunun geridönüşsüz karakter kazanması için geçecek sürenin öngörülmesi mümkün olmaz.
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İSKEMİNİN TEDAVİSİ
•<= /span>Reperfüzyon:
–= Spontan
–= Farmakolojik girişim
–= Cerrahi girişim
•<= /span>İskemik hasar gelişme hızının azaltılması
–= Antiiskemik ajanlar
–= Derlenmeyi hızlandıracak girişimler
–= Endojen yanıtların düzenlenmesi
–
İskemi= k zedelenme gelişmiş bir dokuda nekroza gidişi önlemenin başlıca iki yolu bulunur.
Bunlar= dan ilki  dokunun mümkün olduğu kadar= hızlı bir şekilde yeniden perfüze edilmesidir.
•Bölgesel iskemi ve miyokard infarktüsü du= rumunda reperfüzyonun kendiliğinden oluşması çok seyrek gerçekleşir.
•Pek çok durumda reperfüzyon, trombolitik = ya da cerrahi girişim gerektirir.
•Bu tür girişimler zaman gerektiren  girişimlerdir. Bu nedenle zedelenmenin hızının azaltılmasına yönelik önlemler, iskemi tedavisinin ikinci basamağ= ını oluşturur. Böylece daha fazla hücrenin geri dönebilir zedelenme aşamasında kalması ve reperfüzyon gerçekleştiğinde daha fazla dokunun kazanılması mü= mkün olur
•Bu amaçla antiiskemik ajanlar, miyokardın derlenmesini hızlandıracak girişimler ve endojen (adaptif) yanıtların düzenlenmesine yönelik manüplasyonlar denenebilir.
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İSKEMİK
ZEDELENMENİN YAVAŞLATILMASI
•= Proton ve toksik metabolit birikimi ¯
•= Besin ve enerji tüketimi miktarının değiştirilmesi,
•= Hücresel sodyum ve kalsiyum yükü ¯
•= Potasyum, ko-faktörler ve eser elementlerin = kaybının önlenmesi,
•= Hücre çekirdeği elemanları hasarı ¯
•= Litik enzim aktivasyonu ve lökosit atağının = önlenmesi,
•= Hücre şişmesi ve membran yırtılmasının = engellenmesi.
 İSKEMİ TEDAVİSİ
= Miyokardiyal iskeminin gelişimini yavaşlatmaya yönelik bu girişimlerin  iskemik zedelenmeyi azalttığına ilişk= in çalışmaların varlığına  karşın te= k bir yöntem ile ciddi bir başarı elde edileceğini ummak gerçekçi olmayabilir. = Bu nedenle antiiskemik tedavide birden  fazla yöntemin bir arada kullanılması daha yararlı olabilir.  Tüm bu manüplasyonların başlıca hedef= leri de slaytta görülmektedir.
(1) is= kemi sürecinde gelişen proton ve toksik metabolit birikiminin sınırlanması,
(2) be= sin ve enerji tüketimi miktarının değiştirilmesi,
(3) hü= cresel sodyum ve kalsiyum yükünün manüplasyonu,
(4) po= tasyum, ko-faktörler ve eser elementlerin kaybının önlenmesi,
(5) hü= cre çekirdeği elemanlarının hasarının sınırlandırılması, (6) litik enzim aktivasyonu ve lökosit atağının önlenmesi,
(7) hü= cre şişmesi ve membran yırtılmasının engellenmesi.
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İSKEMİK
ZEDELENMENİN YAVAŞLATILMASI
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Kalsiyum antagonistleri,
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Tamponlar <= /span>
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Osmotik ajanlar=
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Substratlar = ;
<= span class=3DBB style=3D'position:absolute;left:-3.85%'>•Ekstrasellüler = yüksek enerjili fosfatlar
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Magnezyum
 İSKEMİ TEDAVİSİ
= Bu amaçlardan hareket ile pek çok in vivo ve in vitro çalışmada, kalsiyum antagonistleri, buffer’lar, osmotik ajanlar, substratlar, ekstrasellüler yüksek enerjili fosfatlar ve magnezyumun iskemik zedelenmenin miktarını azalttığı, reperfüzyon ile elde edilen derlenmenin miktarını ise arttırdı= ğı gösterilmiştir.
= Bu tür bir yaklaşım kalp cerrahisinde uygulanmakta ve kalbin zarar görmeden iskemik bırakılabileceği süre önemli oranda  uzatılabilmektedir.
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REPERFÜZYON
•Aerobik metabolizma
•Reaktif hiperemi
•Serbest oksijen radikali patlaması
•Adenin nükleotid havuzunda ATP ­
•Laktat ¯
•Doku pH ­
•Kreatin fosfat  ­= 3;
•Doku glikoz düzeyi ­
•=
•=
 İSKEMİ TEDAVİSİ
REP= ERFÜZYONUN ETKİSİ
Kor= oner kan akımının düzelmesi ile iskemik ancak yaşayan miyokard  hücrelerinde aerobik metabolizma yeni= den başlar ve hücreler kurtulur.
Anc= ak dokuda önemli oranda reaktif hiperemi gelişir (%400-600). Reaktif hiperemi reperfüzyonun ilk 5 dakikasında pik yapar ve daha sonra azalır. Reperfüzy= onun sağlanmasından 15-20 dk sonra arteryel kan akımı normal düzeyine ulaşır.<= /b>
Rep= erfüzyonun ilk dakikalarında önemli miktarda serbest oksijen radikali oluşur ve 4-7. dk.da pik düzeyine ulaşır.
Art= eryel reperfüzyonun sağlanmasından 60-120 sn sonra EKG’de iskemik  değişiklikler kaybolur, aynı sürede a= denin nükleotid havuzu içeriği;  (iskemi süresince dokuda birikmiş olan ADP ve AMP’nin refosforilasyonu ile) %90 oranında ATP’ye dönüşmüştür.
Lak= tat hızla kontrol düzeylerine iner,( ya sistemik dolaşıma atılarak ya da CO2 ve H2O= ’ya okside edilerek.)
0.5= -2.0 dk içinde doku pH’sı da normal düzeylerine ulaşır.
Dok= u kreatin fosfat miktarı hızla artar. Doku glikoz düzeyi 4-6 kat yükselir.



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REPERFÜZYON HASARI
•<= /span>Vasküler ve mikrovasküler hasar,
•<= /span>Endotel hücrelerinde disfonksiyon,
•<= /span>Miyositlerde
–= Ödem,
–= Apopitozisde artma,
–= Nekroz miktarında artma
•<= /span>Kardiyak kontraktil disfonksiyon
•
 İSKEMİ TEDAVİSİ
Kısa s= üreli bir miyokard iskemisini takiben reperfüzyonun sağlanması iskemik miyokard dokusunun nekroza gidişini önlerken, nispeten uzun süreli miyokard iskemisinden sonra  reperfüzyonun sağlanması, bir yandan iskemik dokuyu kurtarırken diğer yandan  miyokarda doğrudan kendisi hasar veri= r.
Vaskül= er ve mikrovasküler hasar, endotel hücrelerinde disfonksiyon,
miyosi= tlerde ödem, miyosit apopitozisinde artma,
miyosi= t nekrozunda artış ve kardiyak kontraktil disfonksiyon Vasküler ve mikrovasküler hasar, endotel hücrelerinde disfonksiyon,
miyosi= tlerde ödem, miyosit apopitozisinde artma,
miyosi= t nekrozunda artış ve kardiyak kontraktil disfonksiyon doğrudan reperfüzyonun neden ol= duğu sonuçlardır.

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MEKANİZMA
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 REPERFÜZYON HASARI
Oksidan üretimi
Enflamatuar yanıt
Reperf= üzyon hasarından başlıca iki mekanizmanın sorumlu olduğu kabul edilmektedir:
1. Ser= best oksijen radikali üretimi ve
2. Enf= lamatuar yanıt

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Sarkolemma
Araşidonik
asit
kaskadı
Amino asit
oksidasyonu
Sitokrom
P450
Elektron
transportu
Çekirdek
Mikrozom
= Endoplazmik
= retikulum
Mitokondri
Miyosit
 REPERFÜZYON HASARI
O2-
H2O2
OH-
Pathobiology and Clinical Impact = of Reperfusion Injury
1. OKSİDATİF STRES
2. ENFLAMATUAR YA= NIT
SERBEST
OKSİJEN RADİKALLERİ
= Reperfüzyonun ilk dakikalarında önemli miktarda serbest oksijen radikali oluşur ve 4-7. dk.da pik düzeyine ulaşır.
Ser= best oksijen radikali kaynakları
Mitoko= ndriyal elektron transport sistemi !
Diğer = elektron taşıyıcıları
Mitoko= ndiri iç membranındaki NADH
Endopl= azmik retikulum
Hücre = çekirdeği membranları
Ksanti= n oksidaz
Vaskül= er endotel

Normal= koşullarda O2, mitokondride sitokrom oksidaz sistemince iki elektron kaybederek suya dönüşür.
Bazı d= urumlarda ise oksijen, yüksek oranda reaktif oksijen radikallerine dönüşür:<= br>
1.Süperoksit anyonu O2-
2.Hidrojen peroksit H2O2
3.Hidroksil radikalleri  OH-



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file:///C:/2AC9C632/tark2002_dosyalar/slide0024.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="Windows-1254" KALP İSKEMİSİNDE YENİ BOYUTLAR
SERBEST
OKSİJEN RADİKALLERİ
•<= /span>Hücre membranında peroksidasyon
–= Fosfolipitler
–= Proteinler
•<= /span>Fonksiyon bozukluğu
–= Mitokondri
–= Sarkoplazmik retikulum
1. OKSİDATİF STRES
2. ENFLAMATUAR YA= NIT
 REPERFÜZYON HASARI
= Serbest oksijen radikalleri, çiftlenmemiş elektronları nedeniyle hücre membranında fosfolipidler ve proteinler ile etkileşirler. Tiyol guruplarının oksidasy= on ve peroksidasyonu ile membran yapısının bozulmasına ve çeşitli sellüler proteinlerin disfonksiyonuna neden olurlar.
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ENFLAMATUAR
YANIT
•=
<= span style=3D'font-size:97%;visibility:hidden'>•= 3;
•=
 REPERFÜZYON HASARI
1. OKSİDATİF STRES
2. ENFLAMATUAR YAN= IT
Nötrofiller
Kompleman sistemi
Reperf= üzyon hasarından sorumlu ikinci mekanizma enflamatuar yanıtın tetiklenmesidir. Reperfüzyon sonrasında miyokardiyal inflamatuar yanıtta pek çok faktör yer almaktadır. Bu faktörlerin en önemlilerinden biri nötrofiller, diğeri de kompleman sistemidir.

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NÖT= ROFİLLER
• =
3D"View
Endotel
Endotel
Ekstravazasyon
PECAM-1
Migrasyon
SOR
Proteazlar
Proinflamatuar     medyatörler
Adezyon
İntegrinler
CD11/CD18
ICAM-1
P-selektin
L-selektin
Nötrofiller
Rolling
NO
Adenozin
SOR
PAF
C5a
VDKH
Miyosit
VDKH
Miyosit
ENFLAMATUAR YANIT
1. NÖTROFİLLER
2. KOMPLEMAN AKTİVASYONU
Doku yaralanmasında fizyolojik yanıtı  başlatan ve patojenlere karşı ilk savunma hattını oluşturan nötrofiller reperfüzyonun sağlanması ile aktive olurlar ve hızla  iskemik alana göçerler. Nötrofillerin= bu aktivasyonu, endotel hücrelerine yaklaşmasına, adezyonuna ve transmigrasyonuna neden olur. Nötrofillerin endotele yuvarlanması  endotel hücrelerindeki P-selektinler tarafından ayarlanır. Nötrofillerin endotel hücrelerine yapışmasına ise endotel hücrelerindeki  intersell= üler adezyon molekülü-1 (ICAM-1) ile nötrofillerdeki integrin kompleksi (CD11/CD18) aracı olur. Ekstravazasyon ve transmigrasyon ise endotel hücrelerinin birleşim yerlerinde lokalize olan  platelet endotel hücresi adezyon mole= külü (PECAM-1) tarafından regüle edilir. Transmigrasyonun ardından nötrofiller= bir yandan SOR oluşumuna neden olurken diğer yandan , Elastaz, kollajenaz, jelatinaz gibi Proteinazların; Lökotrien B4, Tromboksan A2, PAF gibi  Proinflamatuar medyatörlerin salıverilmesini kolaylaştırır.
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İSKEMİSİNDE YENİ BOYUTLAR
• =
KOMPLEM= AN SİSTEMİ AKTİVASYONU
ANAFİLATOKSİN OLUŞU= MU
C3a
C4a
C5a
VAZOKONSTRİKSİYON
PERMEABİLİTE
ARTIŞI
ENFLAMATUAR YANIT
1. NÖTROFİLLER
= 2. KOMPLEMAN AKTİVASYONU
KOM= PLEMAN SİSTEMİ AKTİVASYONU
İsk= emi ve reperfüzyon sırasında kompleman sistemi aktive olur.
Akt= ive olan kompleman kaskadı ürünleri (C3a, C4a,C5a) hem vasküler düz kas üzerine he= m de mast hücresi üzerine etkili olarak vazokonstriksiyon ve permeabilite artı= şına neden olur.
Anc= ak klinikte kompleman sisteminin iskemik miyositlerden kaynaklanan bir nedenle mi yok= sa doğrudan SOR tarafından mı aktive edildiği açık değildir.
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<= span style=3D'font-size:89%'>MEMBRAN ATAK KOMPLEKSLERİ
(MAC, C5b-9)
 REPERFÜZYON HASARI
1. OKSİDATİF STRES
2. ENFLAMATUAR YAN= IT
C3a
C4a
C5a
C3
C3b
C5b
C5b67
C5b-9 (MAC)
Membran
C5b
C6
C7
C8
C9
= Kompleman kaskadının aktivasyonu ile 5 terminal protein; C5b, C6, C7, C8 ve C9, birleşerek, hedef hücrenin membranındaki lipid bariyere oturur ve membran atak kompleksi (MAC) oluşturur.
= Membran atak kompleksleri de hücre membranının geçirgenliğini bozarak elektrolit ve sıvıların hücre membranından serbestçe giriş ve çıkışına neden olur.  Hücre içi homeostazının bozulması ile= de hücre ölümüne katkıda bulunur.
= (Hücre membranına saldırma özelliği, Hücre membranında por oluşumu, Kalsiyumun h= ücre içine akışı, Daha önce bahsedilen sürecin işlemesi,
= Hücre membranında yüksek MAC konsantrasyonu ® Sitolizis ® Hücre ölümü)<= /font>

= Miyokard iskemisi ve reperfüzyon sürecinde MAC’nin iskemik ancak yaşayabilir karakterdeki hücreler mi yoksa letal ölçüde zarar görmüş hücrelere mi saldırdığı açık değildir.


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SIN= IFLAMA
•<= /span>Vasküler reperfüzyon hasarı
•<= /span>Reperfüzyon aritmileri
•<= /span>Letal reperfüzyon hasarı
–= Hücre ölümü
•<= /span>Nonletal reperfüzyon hasarı
–= Miyokardiyal stunning
REPERFÜZYON HASARI
Reperf= üzyon hasarı özellikle trombolizis, anjioplasti ve koroner arter cerrahisi gibi klinik durumlarda daha sık görülmektedir.
Her bi= ri ayrı ayrı ya da kombine olarak ortaya çıkabilen 4 klinik tablo ile kendini gösterebilir:
•Vasküler reperfüzyon hasarı
•Reperfüzyon aritmileri
•Letal reperfüzyon hasarı
•Hücre ölümü
•Nonletal reperfüzyon hasarı
•Miyokardiyal stunning

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VASKÜLER
REPERFÜZYON HASARI
•Vaskül= er endotelde progressif hasar
–= Şişme, kabarcıklaşma
–= Yırtılma
–= Nötrofil agregasyonu
–= NO sentezinde inhibisyon
•Korone= r kan akımı rezervinde azalma
•Mikrov= asküler oklüzyon
•No-ref= low fenomeni
1.Va= sküler reperfüzyon hasarı
2.Reperfüzyon aritmileri <= /div>
3.Letal reperfüzyon hasarı =
4.Nonletal reperfüzyon hasarı <= /div>
REPERFÜZYON HASARI
Vaskül= er reperfüzyon hasarı; vasküler endotelde progressif hasar, koroner kan akımı rezervinin bozulması, mikrovasküler oklüzyon sonuçta koroner kan akımının yeniden sağlanmasına karşın “no-reflow”  fenomeni oluşması anlamına gelir.
Reperf= üzyon, endotel tarafından NO sentezlenmesinin inhibisyonu ile sonuçlanır. Ayrıca= hem iskemi hem de ardından gelen reperfüzyon, endotelde kabarcıklaşmalara, yırtılmalara ve nötrofil infiltrasyonuna neden olur (Kısa süreli iskemile= rde nötrofil birikimi olmamakta).
Komşu = miyositlerin kontraktürü ve şişmesi de vasküler rezistansın artmasına katkıda bulunur.Mikrovasküler yataktaki nötrofil, platelet agregatları, reperfüzy= on ile aktive olan çeşitli sitokinler de kan akımının azalmasına neden olabilirler.
Bu fen= omen, deneysel çalışmalarda gösterilmiş olmakla birlikte insanlardaki varlığı kuşkuludur.
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REPERFÜZYON HASARI
REPERFÜZYON
ARİTMİLERİ
•<= /span>Ventriküler aritmiler:
–= Ventrikül taşikardisi
–= Ventrikül fibrilasyonu
•<= /span>Kısa süreli iskemiler (5-15 dk) sonrası
•<= /span>Koroner spazm ile birlikteliği
–= Ani ölüm
•
Lie JT. Cardiova= sc Res 1993;27:1906
1.V= asküler reperfüzyon hasarı
2.Reperfüzyon aritmileri <= /div>
3.Letal reperfüzyon hasarı =
4.Nonletal reperfüzyon hasarı <= /div>
Reperf= üzyonun neden olduğu klinik sorunlar arasında çeşitli aritmiler de sayılabilir. Özellikle açık kalp cerrahisi sırasında sık görülen aritmilerin bir kısmı, reperfüzyon sağlandıktan hemen sonra ortaya çıkmaktadır. Bu tür aritmiler arasında ventrikül fibrilasyonu da bulunabilir. Potansiyel olarak letal özellikte olmasına karşın reperfüzyondan sonra gelişen ventrikül fibrilas= yonu genellikle kendiliğinden sonlanmakta, elektriksel olarak sonlandırılabilm= ekte ya da ilaçlarla önlenebilmektedir.
İskemi= süresinin uzun olması durumunda reperfüzyon aritmilerinin sıklığı azalmaktadır.
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LETAL
REPERFÜZYON HASARI=
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Reperfüzyon ® hücre ölümü = 3;
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•İnsan çalışmala= rında ?
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Çelişkili veril= er ?
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Apopitozisin ro= lü ?
<= span style=3D'visibility:hidden'>•
1.V= asküler reperfüzyon hasarı
2.Re= perfüzyon aritmileri
3.Letal reperfüzyon hasarı =
4.Nonletal reperfüzyon hasarı <= /div>
REPERFÜZYON HASARI
LETAL = REPERFÜZYON HASARI
Nispet= en uzun süren bir iskemiden sonra reperfüzyonun kendisinin yaşayan miyokard hücrelerinin ölmesine neden olmasına ilişkin çok sayıda deneysel kanıt bulunmasına karşın klinik çalışmalarda benzer bilgilere ulaşmak mümkün olamamaktadır.
Letal = reperfüzyon hasarında apopitozisin rolü hakkında daha sonraki slaytlarda konuşacağız.=
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= NONLETAL
REPERFÜZYON HASARI
Kısa süreli=
oklüzyon
Reperfüzyon
Bölgesel du= var hareketi anormalliği
Uzun süren =
derlenme
1.V= asküler reperfüzyon hasarı
2.Re= perfüzyon aritmileri
3.Le= tal reperfüzyon hasarı
4.Nonletal reperfüzyon hasarı <= /div>
REPERFÜZYON HASARI
(MİYOKARDİYAL STUNNING)
•MİYOKARDİYAL STUNNİNG
•Bu klinik tabloda nekroz gelişmemiş olmasına karşın reperfüzyondan sonra uzayan bir kontraktil işlev bozukluğu gözlenir.
•Miyokardiyal iskemi durumunda, bölg= esel sol ventrikül duvar hareketleri azalır. Eğer kalp total olarak iskemik kalırs= a, tüm kalpte kontraktil disfonksiyon oluşacaktır. İskeminin giderilmesi ile (spazmın çözülmesi, trombüsün lizisi, miyokardın oksijen gereksiniminin azaltılması vb.) iskemik ancak yaşayan miyokard dokusu düzelir ancak kontraktil disfonksiyonun tamamen düzelmesi saatler ya da günler alabilir= .
Geri d= önüşlü bir karakterde olmasına karşın miyokardiyal stunning, sol ventrikül yetersizliğine neden olarak morbidite ve mortaliteyi arttırabilen önemli = bir klinik sorundur.

•Kontraktil fonksiyonun düzelmesi iç= in gereken süre, iskemik dönemin süresine, ciddiyetine ve arteryel akımın yeterliliğine bağlıdır.
•Reperfüzyonun sağlanmasından sonra = gözlenen bu kontraktil fonksiyon yetersizliği ilk kez 1970’lerde Heyndrickx tarafı= ndan tanımlanmıştır.Daha sonra Braunwald ve Kloner, stunning ismi verilmiştir.=
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STU= NNING MEKANİZMASI
•Serbest radikaller ve oksidan stres
•Kalsiyum homeostazında düzensizlik
<= span style=3D'font-size:88%'>•Kontraktil proteinin kalsiyum duyarlılığı
•Adenozin trifosfat resentezinin bozulması
•Fonksiyonel sempatik denervasyon
•Heterojen bir reperfüzyon
•Kreatin kinaz aktivitesinin kaybı
•Miyokardiyal kollajen zedelenmesi
<= span style=3D'font-size:88%;visibility:hidden'>•
<= span style=3D'font-size:156%;color:#333399;mso-color-index:5'>•Serbest radikaller ve oksidan stres&= #13;
<= span style=3D'font-size:156%;color:#333399;mso-color-index:5'>•Kalsiyum homeostazında düzensizlik&#= 13;
<= span style=3D'font-size:156%;color:gray;mso-color-index:2'>•Kontraktil proteinin kalsiyum duyarlılı= ğı
•Adenozin trifosfat resentezinin bozulması
<= span style=3D'font-size:156%;color:gray;mso-color-index:2'>•Fonksiyonel sempatik denervasyon
<= span style=3D'font-size:156%;color:gray;mso-color-index:2'>•Heterojen bir reperfüzyon
<= span style=3D'font-size:156%;color:gray;mso-color-index:2'>•Kreatin kinaz aktivitesinin kaybı <= /span>
<= span style=3D'font-size:156%;color:gray;mso-color-index:2'>•Miyokardiyal kollajen zedelenmesi <= /span>
<= span style=3D'font-size:156%;color:gray;mso-color-index:2;visibility:hidden'>•=
STUNNI= NG’İN MEKANİZMASI
(Stunn= ed miyokardın bir özelliği, inotropik uyarıya yanıt vermesidir. )
Geri d= önüşlü bir karakterde olmasına karşın miyokardiyal stunning, sol ventrikül yetersizliğine neden olarak morbidite ve mortaliteyi arttırabilen önemli = bir klinik sorundur.
Özelli= kle kalp cerrahisi ve transplantasyon sonrasında önemli olmasına karşın anjina, başarılı bir tromboliz ve  yoğun = bakım hastalarında  miyokardın oksijen gereksiniminin artması ya da sunumunun azalması ile tetiklenen miyokard iskemisi sonrasında da gelişebilir.
Bu ned= enle miyokardiyal stunningin arkasında yatan mekanizmalara ve tedavisi ya da önlenmesine ilişkin tedavi modelleri artık daha çok araştırılmaya başlamıştır.
Stunni= ng, bir reperfüzyon hasarı olduğuna göre altta yatan mekanizma için reperfüzyon hasarını açıklamak için kullanılan mekanizmalaardan bahsedilebilir. Ancak serbest oksijen radikalleri ve kalsiyum homeostazındaki düzensizlik en çok kabul gören açıklamalar olmaktadır.

Stunni= ngin mekanizmasına ait tüm bilgilerimiz, büyük hayvan çalışmalarından gelmekte= dir.

Stunni= ng mekanizmasının %50-70’inden, reperfüzyonun ilk dakikalarında oluşan serbe= st oksijen radikali patlaması sorumludur.
SOD ve= katalaz gibi radikal süpürücülerin kullanılması ile stunningin önemli oranda önlenmesi bu hipotezi desteklemektedir.Ancak tamamen önlenememesi de iske= mi süresince gelişen doku hasarının da sorumluluğunu göstermektedir. Ayrıca klinik çalışmalarda radikal temizleyicilerin kontraktil fonksiyonda önemli bir düzelme sağlamaması da dikkat çekicidir.
Ayrıca= Ca++ homeostazı ve kontraktil organellerin Ca++’a duyarlılığındaki değişiklikl= er de olası mekanizmalar arasında olabilir.

Miyoka= rdiyal stunning gelişiminden sorumlu olduğu düşünülen diğer mekanizmalar arasınd= a
(1) ad= enozin trifosfat resentezinin bozulması,
(2) fo= nksiyonel sempatik denervasyon
(3) he= terojen bir reperfüzyon,
(4) kr= eatin kinaz aktivitesinin kaybı,
(5)miy= okardiyal kollajen zedelenmesi,
yer al= maktadır.

------=_NextPart_01C2E70A.04E4FC00 Content-Location: file:///C:/2AC9C632/tark2002_dosyalar/slide0044_image146.gif Content-Transfer-Encoding: base64 Content-Type: image/gif R0lGODlh4gEKAXcAMSH+GlNvZnR3YXJlOiBNaWNyb3NvZnQgT2ZmaWNlACH5BAEAAAAALAAAAADg AQgBgAAAAP///wL/jI+py+0Po5y02ouz3rz7D4biSJbmiabqyrbuC8fyTNf2jef6zvf+DwwKh8Si 8YhMKpfMpvMJjUqn1Kr1is1qt9yu9wsOi8fksvmMTqvX7Lb7DY/L5/S6/Y7P6/f8vv8PGCg4SFho eIiYqLjI2Oj4CBkpOUlZaXmJmam5ydnp+QkaKjpKWmp6ipqqusra6voKGys7S1tre4ubq7vL2+v7 CxwsPExcbHyMnKy8zNzs/AwdLT1NXW19jZ2tvc3d7f0NHi4+Tl5ufo6err7O3u7+Dh8vP09fb3+P n6+/z9/v/w8woMCBBAsaPIgwocKFDBs6fAgxosSJFCtavIgxo8aN/hw7evwIMqTIkSRLmjyJMqXK lSxbunwJM6bMmTRr2ryJM6fOnTx7+vwJNKjQoUSLGj2KNKnSpUybOn0KNarUqVSrWr2KNavWrVy7 ev0KNqzYsWTLmj2LNq3atWzbun0LN67cuXTr2r2LN6/evXz7+v0LOLDgwYQLGz6MOLHixYwbO34M ObLkyZQrW76MObPmzZw7e/4MOrTo0aRLmz6NOrXq1axbu34NO7bs2bRr276NO7fu3bx7+/4NPLjw 4cSLGz+OPLny5cybO38OPbr06dSrW7+OPbv27dy7e/8OPrz48eTLmz+PPr369ezbu38PP778+fTr 27+PP7/+6wUAADs= ------=_NextPart_01C2E70A.04E4FC00 Content-Location: file:///C:/2AC9C632/tark2002_dosyalar/slide0045.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="Windows-1254" KALP İSKEMİSİNDE YENİ BOYUTLAR
REPERFÜZYONDA KORUYUCU YAKLAŞIMLAR-I
•= Ekstrasellüler elektrolit modifikasyonları, <= /span>
–= Potasyum,
–= Kalsiyum,
–= Sodyum ve magnezyum
•= Substrat varlığı ve kullanımının manüplasyonu =
–= Glutamat,
–= Aspartat veya
–= Piruvat
•= Serbest radikaller ve oksidan stresin kontrolü, &#= 13;
–= Süperoksit dismutaz,
–= Katalaz,
–= Vitamin E ve C 
–= Allopurinol
Reperf= üzyon anında yapılan bazı girişimlerin iskemik derlenmeyi hızlandırabildiği gösterilmiştir. Bu tür reperfüzyon girişimleri arasında (1) ekstrasellüler potasyum, kalsiyum, sodyum ve magnezyum modifikasyonları, (2) glutamat, aspartat veya piruvat gibi ajanlar ile substrat varlığı ve kullanımının manüplasyonu, (3)  süperoksit dis= mutaz, katalaz, vitamin E ve C ve allopurinol gibi ajanlar ile serbest radikalle= r ve oksidan stresin kontrolü,
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REPERFÜZYONDA KORUYUCU YAKLAŞIMLAR-II
•Fiziksel faktörlerin manüplasyonu,
–Oksijen basıncı
–Sıcaklı= k
–Osmolar= ite
–pH = ;
•Kan kay= naklı elemanların kontrolü,
–Lökosit= ve platelet gibi
•Vazoakt= if ajanlar
–Adenozi= n, nitratlar ve dipridamol
–
(4) ok= sijen basıncı, sıcaklık, osmolarite ve pH gibi fiziksel faktörlerin manüplasyon= u, (5) lökosit ve platelet gibi kan kaynaklı elemanların kontrolü, (6) adeno= zin, nitratlar ve dipridamol gibi vazoaktif ajanların kullanılması ile koroner= kan akımının arttırılması ve dağılımının düzenlenmesi gibi girişimler sayılabilir.
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ENDOJEN YANITLARIN DÜZENLENMESİ
•Stres proteinler
–Streste= n 24 saat sonra pik
–Kalbin iskemiye direncinde artış
–Mekaniz= ma ?
•İskemik önhazırlama
REPERFÜZYON HASARI
End= ojen yanıtların düzenlenmesi
Rep= efüzyon hasarının önlenmesine yönelik olarak en heyecan verici yaklaşım ise kalbin iskemiye karşı kendisini koruma yeteneğinin keşfedilmesi ile gelişmiştir.= Bu tür koruyucu yaklaşımlar, endojen adaptif yanıtların manüplasyonunu hedef= ler ve şu an bu konuda  ilgi çeken ba= şlıca iki kavram bulunmaktadır: (1) Stres proteinler ve (2) iskemik önhazırlama kavramı
Str= es proteinler:
Kal= bin bazı stres yanıt proteinlerini oluşturarak çeşitli stres dönemlerine yanıt ver= diği bilinmektedir. Bu proteinler, stresin başlamasından yaklaşık 24 saat sonra maksimal düzeye ulaşmakta ve kalbin iskemik zedelenmeye direncini arttırmaktadır. Altta yatan mekanizma iyi bilinmemekle birlikte bu tür bir girişimin iskemik kalbin korunmasında kullanılmasına yönelik çalışmalara = konu olması mümkün görülmektedir.

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İSKEMİK ÖNHAZIRLAMA
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Murry, 1986 = ;
<= span class=3DBB style=3D'position:absolute;left:-4.43%'>•Köpek çalışması=
İskemi
Reperfüzyon
İskemi
Reperfüzyon
İskemi
Reperfüzyon
İskemi
Reperfüzyon
(40 dk)
İskemi
(40 dk)
İskemi
= İSKEMİK ÖNHAZIRLAMA
= TANIM VE BİYOLOJİ
= Geçici miyokard iskemisi atakları bir yandan miyokard dokusunda geçici hasar oluşturma özelliği taşırken diğer yandan kalbi nekroz gelişme tehlikesind= en de koruyabilir.İskemik önhazırlama tanımı ilk kez Murry tarafından ortaya konulmuştur.  1986’da 40 dk sürey= le koroner oklüzyon geliştirilen köpeklerde gelişen nekroz alanına göre, oklüzyon öncesinde 5’er dk aralıklar ile 4  kez uygulanan 5 dk.lık iskemik dönemlerin nekroz alanını önemli or= anda azalttığı gösterilmiştir.Önhazırlama daha sonra başka hayvan kalplerinde = de gösterilmiştir.
= İskemik önhazırlama, 5 dk.lık reperfüzyonlar ile kesilen 3-5 dk gibi kısa süreli iskemik dönemlerin oluşturulması ile sağlanabilir (klasik, erken önhazırlama). Ancak tek bir iskemik dönemin de aynı sonucu sağlayabileceği düşünülmektedir.
İskemi= k ön hazırlama ile nekroz oluşturabilecek ciddiyette bir iskemi süreci arasınd= aki süre 5 dk.dan 3 saate çıkarıldığında iskemik önhazırlamanın olumlu etkisi kaybolmaktadır. Ancak bu ara, 24-96 saate uzadığında koruyucu etki yeniden geri dönmektedir. Bu etkiye önce “2.koruma penceresi” adı verilmiş daha sonra ise “gecikmiş ya da geç iskemik önhazırlama” olarak adlandırılmaya başlamıştır.
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