**4.3 Transthoracic Doppler sampling of LAD blood velocities and other methods**

Measurement of coronary flow velocities using Doppler wire and pressure recordings to assess severity of coronary artery and microcirculation are invasive procedures in addition to other disadvantage (Iliceto et al 1991; Erbel et al, 1991; Kozakova et al, 1994; Donohue et al, 1993; Miller et al, 1994; Di Carli et al, 1995). Normal peak diastolic velocities in the present study were similar to those reported previously by invasive Doppler flowires (Ofili et al, 1993).

Trans-esophageal echocardiography visualizes only the proximal coronary arteries and Doppler sampling is feasible in less than 70% of patients (Joye et al, 1994; Kern et al 1995; Abizaid et al, 1998). Recent technologic advances in trans-thoracic echocardiography made Doppler sampling of coronary artery velocities possible (Voci et al, 1998; Caiati et al, 1999; Hildick-Smith et al, 2000; Higashiue et al, 2001; Pizzuto et al, 2001; Takeuchi et al, 2001). Contrast agents may enhance the detection rate of coronary velocities (Abizaid et al, 1998; Caiati et al, 1999), however, with increasing experience of the operator contrast agents are not needed.

## **4.4 Validity of LAD blood velocities and flow calculations**

The range of the value of LAD blood velocities and time velocity integrals (Sharif et al, 2010) is similar to those found through cardiac valves with similar reproducibility and applicability. The diameter of the LAD and of the colour jet of blood flow through the vessel is in the range of diameter of vena contracta of regurgitant jets through cardiac valves. Moreover, LAD-colour jet diameter is similar to that of proximal iso-velocity surfaces of regurgitant jets through the mitral valve, so it can be applied in a similar fashion and

Effects of Eptifibatide on the Microcirculation After Primary Angioplasty in

Glycoprotein IIbIIIa receptor blockers fulfil these requirements.

reveal such benefit in recovering left ventricular systolic function.

**5. Summary and look to the future** 

primary angioplasty.

**6. References** 

**STEMI** 

**4.8 The logic and need for intense antiplatelet treatment in acute STEMI** 

Acute ST-Elevation Myocardial Infarction: A Trans-Thoracic Coronary Artery Doppler Study 71

Plaque disruption is considered to be the common substrate of acute coronary syndromes (Boersma et al, 2003). Consequently, the blood is exposed to a significant quantity of thrombogenic materials initiating platelet aggregation and the lumen of the coronary artery become obstructed by a combination of platelets, fibrin and red blood cells. Moreover, as mentioned previously, primary coronary angioplasty in patients with acute STEMI is associated with microembilzation rich with platelets to the distal coronary circulation. Therefore, the administration of rapidly acting powerful antiplatelet agent seems logical.

**4.9 The evidence of effectiveness of Glycoprotein IIbIIIa receptor blockers in acute** 

Thus, Abciximab (Neumann et al, 1998) maintained patency of large coronary arteries, but in addition was associated with higher coronary artery peak blood velocities and better left ventricular wall motion score index and higher left ventricular ejection fraction compared to heparin. Abciximab (de Lemos et al, 2000) was shown to improve both epicardial coronary artery flow and myocardial reperfusion as evidenced by resolution of ST elevation in patients with acute STEMI. Eptifibatide and tirofiban- small molecule Glycoprotein IIbIIIa receptor blockers- in a meta-analysis study were shown to be non-inferior to abciximab in patients with acute STEMI undergoing PPCI (Ottani et al, 2010). Eptifibatide was shown to be equal to abciximab as an adjunct to PPCI in acute STEMI and as effective in causing resolution of ST elevation ( Zeymer et al, 2010) and reduced the rate one year mortality and re-infarction ( Akerblom et al, 2010). Eptifibatide improved clinical outcome in patients with STEMI undergoing PPCI (Mahmoudi et al, 2011). In our study eptifibatide prevented severe dysfunction of coronary microcirculation after PPCI in acute STEMI which was not translated into better left ventricular systolic function. A larger number of patients may

Thus, transthoracic Doppler echocardiography is feasible and provides important information about the function of coronary microcirculation in patients with acute STEMI undergoing PPCI. Treatment with eptifibatide before primary angioplasty, prevented early LAD systolic flow reversal indicative of severe dysfunction of the microcirculation, increased diastolic LAD velocities and flows but did not increase left ventricular systolic function. Understanding mechanisms of dysfunction of the coronary microcirculation and implementation of newer strategies to treat microcirculatory dysfunction with transthoracic Doppler evaluation may improve the treatment of patients with acute STEMI undergoing

Abizaid, A.; Mints, G.S.; Pichard, A.D.;Kent, K.M.; Satler, L.F.; Walsh, C.L.; Popma, J.J. &

transluminal coronary angioplasty. *Am J Cardiol*, Vol, 82, pp. 423-428.

Leon, M.B. (1998). Clinical, intravscular ultrasound, and quantitaive angiographic determinants of the coronary flow reserve before and after percutaneous

squared to calculate areas. Thus if blood velocities, and colour jet diameters of the LAD are similar to those of cardiac valves, then flow calculations should be of the same degree of validity.

## **4.5 Need for coronary blood velocity sampling in acute STEMI**

Restoration of epicardial coronary artery flow by primary PCI in the setting of acute STEMI improves outcome (Shah et al, 2000), however optimization of myocardial tissue perfusion improves the prediction of outcome (van't Hof et al, 1998; Shah et al, 2000; van't Hof et al, 1997; Claeys et al, 1999; The TIMI Study Group, 19985; Gibson et al, 1996; 1999; 2001; de Lemos, 2001; Dörge et al, 2000). Despite these findings, still even with successful primary PCI and the high rate of patency of the culprit artery, left ventricular functional recovery is limited and not well predicted (Stone et al, 1997; Zijlstra et al, 1997).

 Despite the value of myocardial blush grade in the evaluation of myocardial perfusion it is not repeatable because of its invasive nature. Resolution of ST-elevation also correlates with better myocardial perfusion, however it reflects only the stage immediately following the emergency PCI. As we have shown (Sharif et al, 2008) the function of coronary microcirculation is variable and may improve or worsen during the hospital stay after primary coronary angioplasty in patients with acute STEMI. Therefore, Doppler transthorcaic sampling of LAD blood velocities is important in such patients.

#### **4.6 Diastolic deceleration time of LAD blood velocity curve (DDT) and the microcirculation**

To understand the relation between DDT and coronary microcirculation, consider normal subjects where the intra-myocardial blood capacitance vessels fill during diastole without significant increase in intramural pressure, therefore the DDT is prolonged. When the capacitance vessels are partially obstructed with miroemboli there is impedance to flow in diastole, therefore the DDT is abbreviated (Kawamoto et al, 1999; Yamamaro et al, 2002). When the blockage of the microcirculation is more severe, the milking of blood in systole cannot proceed to the venules; instead, it is pushed back into the coronary artery and results in early systolic flow reversal (Kawamoto et al, 1999; Yamamaro et al, 2002).

#### **4.7 Mechanisms of dysfunction of coronary microcirculation after primary coronary angioplasty**

After primary PCI, dysfunction of the microcirculation may develop as a result of periprocedural microembolization to the distal coronary artery bed. In addition, recently, evidence for the hypothesis that in situ inflammation and thrombosis contributes to dysfunction of the microcirculation after primary PCI was provided (Dörge et al, 2000). Despite the tendency of microemboli to dissolve after they developed during primary PCI, in situ microcirculatory thrombosis may account for worsening of microcirculatory function late after primary PCI. Thus not only early evaluation of the coronary microcirculation is important; in fact the worst coronary microcirculatory status like minimal diastolic deceleration time of LAD blood velocity seems to be even more important.

#### **4.8 The logic and need for intense antiplatelet treatment in acute STEMI**

Plaque disruption is considered to be the common substrate of acute coronary syndromes (Boersma et al, 2003). Consequently, the blood is exposed to a significant quantity of thrombogenic materials initiating platelet aggregation and the lumen of the coronary artery become obstructed by a combination of platelets, fibrin and red blood cells. Moreover, as mentioned previously, primary coronary angioplasty in patients with acute STEMI is associated with microembilzation rich with platelets to the distal coronary circulation. Therefore, the administration of rapidly acting powerful antiplatelet agent seems logical. Glycoprotein IIbIIIa receptor blockers fulfil these requirements.

#### **4.9 The evidence of effectiveness of Glycoprotein IIbIIIa receptor blockers in acute STEMI**

Thus, Abciximab (Neumann et al, 1998) maintained patency of large coronary arteries, but in addition was associated with higher coronary artery peak blood velocities and better left ventricular wall motion score index and higher left ventricular ejection fraction compared to heparin. Abciximab (de Lemos et al, 2000) was shown to improve both epicardial coronary artery flow and myocardial reperfusion as evidenced by resolution of ST elevation in patients with acute STEMI. Eptifibatide and tirofiban- small molecule Glycoprotein IIbIIIa receptor blockers- in a meta-analysis study were shown to be non-inferior to abciximab in patients with acute STEMI undergoing PPCI (Ottani et al, 2010). Eptifibatide was shown to be equal to abciximab as an adjunct to PPCI in acute STEMI and as effective in causing resolution of ST elevation ( Zeymer et al, 2010) and reduced the rate one year mortality and re-infarction ( Akerblom et al, 2010). Eptifibatide improved clinical outcome in patients with STEMI undergoing PPCI (Mahmoudi et al, 2011). In our study eptifibatide prevented severe dysfunction of coronary microcirculation after PPCI in acute STEMI which was not translated into better left ventricular systolic function. A larger number of patients may reveal such benefit in recovering left ventricular systolic function.
