Učinak koštanoga morfogenetskoga proteina na remodeliranje miokarda u modelu akutnoga infarkta miokarda u štakora [Bone morphogenetic protein impact on myocardial remodelling in acute myocard infarction rat model]

Cvjetičanin, Bruno (2015) Učinak koštanoga morfogenetskoga proteina na remodeliranje miokarda u modelu akutnoga infarkta miokarda u štakora [Bone morphogenetic protein impact on myocardial remodelling in acute myocard infarction rat model]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Myocardial infarction (MI) is the leading cause of death in both men and women and represents one of the most severe health problem in a modern world. Myocardial necrosis is caused by critical imbalance between the coronary oxygen supply and the demand of the myocardium. Heart failure after MI is a common clinical syndrome with high mortality. Left ventricular remodeling after MI involves expansion of the infarcted area, ventricular dilatation and thinning of the ventricular wall. The main goals of standard therapy are rapid thrombolysis, optimization of oxygen, reduction of cardiac workload and pain control. There is great need for novel, powerful antifibrotic therapy. Bone morphogenetic proteins (BMP) are molecules discovered in bones and other different tissues. BMP1 isoforms were discovered in healthy humans and in patients with numerous diseases. In rats with chronic kidney disease administration of BMP1-3 increased renal fibrosis, while therapy with BMP1-3 neutralizing antibody reduced renal fibrosis. BMP1 isoforms were also identified in patients with acute myocardial infarction. We succeeded in performing the inhibition of the BMP1-3 isoforme with specific antibody as a key role molecule in fibrose process in an acute myocardial infarction in rats. Our results confirmed high efficiency in reducing the area of the heart muscle affected by fibrous changes, noted reduced effect of heart remodeling as well as a significant improvement in heart function. We evaluated the therapy by using the measurement of cardiac enzyme levels, echocardiographic analysis of cardiac function and histological analysis of the heart muscle after coronary artery ligation and initiation of the therapy.

Abstract in Croatian

Infarkt miokarda vodeći je uzrok smrti u muškaraca i žena te predstavlja jedan od najznačajnijih zdravstvenih problema razvijenog svijeta. Nekroza miokarda događa se zbog neravnoteže između potrebe miokarda za kisikom i opskrbe koju osigurava koronarna cirkulacija. Srčano zatajenje nakon infarkta miokarda uobičajeno je kliničko stanje s visokom smrtnošću. Opisana je uska povezanost između srčanog zatajenja i procesa remodeliranja miokarda. Glavni ciljevi postojeće terapije jesu brza tromboliza, opskrba kisikom, redukcija srčanog rada i kontrola boli. Postoji velika potreba za novom, snažnom antifibrotičnom terapijom. Koštani morfogenetski proteini (BMP) skupina su molekula otkrivena prvenstveno u koštanom, ali i u drugim tkivima. Izoforme BMP1 otkrivene su u zdravih dobrovoljaca i bolesnika s raznim morbiditetima. U štakora s kroničnim bubrežnim zatajenjem BMP1-3 potiče renalnu fibrozu, dok terapija s neutralizirajućim BMP1-3 protutijelom reducira fibrozu bubrega. BMP1 izoforme također su otkrivene u krvi pacijenata s akutnim infarktom miokarda. Uspjeli smo dokazati uspješnost inhibicije BMP1-3 specifičnim protutijelom, kao ključne molekule u procesu fibroze u modelu akutnog srčanog infarkta u štakora . Rezultati su pokazali smanjenje veličine srčanog mišića zahvaćene fibroznim promjenama, smanjene posljedice remodeliranja miokarda kao i značajno poboljšanje funkcije srca. U evaluaciji terapije koristili smo analizu srčanih enzima u serumu, ehokardiografsku obradu funkcije srca i histološku analizu preparata srčanog mišića nakon podvezivanja koronarne arterije i početka terapije.

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