Recurrent Myocardial Infarction: New Concepts in Predisposing Factors

At one end of the clinical spectrum of coronary arterydisease (CAD) are subjects who have had repeated acuteischemic events (unstable angina, acute myocardial infarctionor sudden death), and at the other end are those with longstandingstable angina who have never been unstable. Thevariability of serum level of thrombomodulin (TM) in variousphases of ischemic heart disease (IHD) raised the question ofvariable pathphysiological role as vasoprotective, thromboresistant,and anti-inflammatory factor. To answer the questionof TM variable levels in IHD, we studied 100 patients (90males and 10 females, mean age 57± 11.3 range 38 to 69years,) with IHD including 5 groups (20 pts for each), RecurrentMI (RMI), Old stable MI (OSMI), Stable Angina (SAP),Acute MI (AMI), and a control group (normal coronary angiography).Methods: Following clinical examination TM level wasdetermined using ELIZA technique. Genetic studies usingsingle strand conformation polymorphism (SSCP) methodwas done to determine mutation in TM gene G-33 A.Results: Compared to control group, patients with IHDhad significantly lower TM level (5.7±3.6 VS 3.06±2.8;p=0.002). Serum TM in patients with SAP was significantlylower compared to control subjects (5.7±3.6 VS 3.92±2.8;p=0.004).Compared to pts with OSMI., Pts with RMI had significantlyhigher levels of TM (4.52±4.3 VS 5.85± 3.8; p= 0.031).Compared to pts with SAP, Pts with OSMI had significantlyhigher level of TM (3.06± 2.8 VS 4.52±4.3; p= 0.003).In ischemic pts, there is a constant tendency of increasedTM level from SAP to OSMI to RMI (3.06±2.8, 4.52±4.3 and5.85±3.8, respectively). There was no significant differencebetween pts with RMI and the control group (5.85±3.8 VS5.7±3.6; p=0.93). Compared to control group, Pts with AMIhad significantly lower level of TM (2.8±2.1 VS 5.7±3.6; p=0.0001) and significantly lower level of TM compared to ptswith IHD not in the acute stage (p=0.026). Regarding TMgene mutation, this study revealed that patients with a mutantTM gene have a significantly less TM level compared topatients with the mild type TM gene (2.85±2.1 vs 4.7±3.6,p=0.04) with the consequences of decreased surface expressionof TM and decreased level of soluble TM in plasma.Conclusion: Our data point to the duality of the role ofthrombomodulin in IHD as a thromboresistant and antiinflammatorymolecule. Reduced serum levels of TM couldpredispose to IHD and acute MI. Higher TM levels in normalpopulation reflect activation of thrombin through protein Cpathway activation (antithrombotic mechanism) whereas thelower levels of thrombomodulin in stable angina and acuteMI might reflect a deficient anti thrombotic mechanism andmay speak of the underestimated anti inflammatory role ofthrombomodulin knocked down by inflammatory mediatorsreleased in the ischemic process. Recurrence of MI mightexplain the high levels of TM which serves as endothelialanti-inflammatory maker which is signaled by the continuedinflammatory state caused by recurrent MLThe reduced TM expression on the coronary endotheliumcould facilitate thrombus formation at the site of plaque injury,highlighting the cardioprotective role played by TM at thecoronary vasculature.