Murat Sezer, Emre Aslanger, Arif Cimen, Ebru Yormaz, Cuneyt Turkmen, Berrin Umman, Yılmaz Nisanci, Zehra Bugra and Sabahattin Umman Istanbul University, Istanbul Faculty of Medicine, Department of Cardiology Istanbul - Turkey Sezer, M. et al. Circ Cardiovasc Interv 2010;3:

Background: Epicardial coronary artery occlusion is accompanied by microvascular damage during the course of ST elevation acute myocardial infarction (STEMI). Degree of microvascular destruction is associated with the extent of infarction after STEMI. Over time after reperfused STEMI, microvascular function is restored in the infarcted territory and infarct size decreases. However, connection between the course of microvascular and infarct remodeling processes over time after reperfused STEMI has not been fully elucidated.

Hypothesis: We hypothesized that improvement in microvascular function over time after reperfused STEMI is related to the infarct healing process.

Aim: This study examines the association of temporal changes in hemodynamics of microcirculation in the infarcted territory and in infarct size (IS) which were assessed simultaneously in the sub- acute phase and at long-term follow-up in patients who were successfully treated with primary percutaneous coronary intervention for STEMI.

Methods: 1. Evaluation of Microvascular Perfusion  Pressure-temperature sensor-tipped guide wire (Pressure wire sensor 5, Radi Medical Systems, Uppsala, Sweden) was used.  Thermodilution-derived Coronary Flow Reserve (CFR)* = Resting mean transit time / hyperemic mean transit time *Pijls NHJ et al.. Circulation 2002;105:  Index of Microvascular Resistance (IMR)**: = Distal coronary pressure x hyperemic mean transit time **Fearon WF. et al.. Circulation. 2003;107: Evaluation of Microvascular Perfusion  Pressure-temperature sensor-tipped guide wire (Pressure wire sensor 5, Radi Medical Systems, Uppsala, Sweden) was used.  Thermodilution-derived Coronary Flow Reserve (CFR)* = Resting mean transit time / hyperemic mean transit time *Pijls NHJ et al.. Circulation 2002;105:  Index of Microvascular Resistance (IMR)**: = Distal coronary pressure x hyperemic mean transit time **Fearon WF. et al.. Circulation. 2003;107: Sezer, M. et al. Circ Cardiovasc Interv 2010;3: The patients underwent coronary angiography and microvascular function assessment at two days ( hours, n=52) and 5 - month ( weeks, n=43) after the acute event.

2. Infarct size assessment Resting technetium – 99m sestamibi SPECT studies were performed days after primary PCI (n=52) and at 5th month ( weeks) in follow-up (n=43). 3. Echocardiographic analysis Left ventricular end-systolic (LVESV) and end-diastolic volumes (LVEDV) and ejection fraction (LVEF, area-length method) were measured by echocardiography at 4 days and at 5 months.

Statistical analysis: Univariable linear regression analysis was used to evaluate the relationship between relative changes in measures of microvascular function (CFR, IMR) from baseline to long term follow-up and IS. Multivariable linear regression analysis was applied to identify the independent predictors of relative change in IS including baseline IS, pain-to balloon time, blood pressure, blood glucose level at admission and, change in measures of microvascular function into the model. Partial correlation analysis with controlling of early-phase (4 th day) IS was also performed to examine the independent relations between baseline microvascular perfusion parameters and long term IS (5 th month) and relative change in IS and relative change in microvascular perfusion parameters. The two groups were identified according to mean value of relative change in CFR and IMR: in whom percent change in improvement in CFR or IMR from baseline to 5 months follow-up were below the mean; and in whom percent change in improvement in CFR or IMR from baseline to 5 months follow-up were above the mean. Comparison of the mean value of relative changes in IS, LVEDV, LVESV, and LVEF from baseline to 5 th month follow-up between the two groups were performed by using independent t test.

52 STEMI patients Death 1 pt Refused 8 pts Two days after primary PCI (n=52) Microvasc. Evaluation Infarct size assessment Echocardiography Study patients: Restenosis in IRA 8 pts Follow-up (5- months) (n=43) Control angiography & Microvasc. Evaluation Infarct size assessment Echocardiography Final study population  35 patients who had both of the first and second SPECT imaging, measures of microvascular function and echocardiographic evaluations.

All Patients Infarct SizeCoronary Flow ReserveIndex of Microvascular Resistance Below mean (n:16) Above mean (n:19) p (BM vs AM) Below mean (n:19) Above mean (n:16) p (BM vs AM) Below mean (n:14) Above mean (n:21) p (BM vs AM) Baseline Characteristics Age, years ± ± ± ± ± ± Male, n (%) 26 (74)10 (66%)16 (84%) (68%)13 (81%)0.469 (64%)17 (80%)0.43 Smoking, n (%) 24 (68)11 (68%)13 (68%) (63%)12 (75%) (78%)13 (62%)0.46 Hypertension, n (%) 20 (57)7 (43%)13 (68%) (58%)9 (56%) (71%)10 (48%)0.29 Hyperlipidemia, n (%) 20 (57)8 (50%)12 (63%) (52%)10 (62%)0.738 (57%)12 (57%)1.00 Diabetes Mellitus, n (%) 12 (34)7 (44%)5 (26%)0.317 (36%)5 (31%)1.006 (42%)6 (29%)0.47 Infarct Characteristics Anterior MI, n (%) 20 (57)9 (56%)11 (58%) (63%)8 (50%)0.507 (50%)13 (62%)0.51 Pain-to-balloon time, min ±115197± ±119218± ±120198± MVD, n (%) 9 (25)4 (25%)5 (26%)1.006 (31%)3 (19%)0.463 (21%)6 (28%)0.48 STR, % ± ± ±1878± ±1776± Hemodynamics Heart rate, mean ± ± ± ± ± ± Blood pressure, mean ± ± ± ± ± ± Tmn Baseline, (sec.) ± ± ± ± ± ± CFR Baseline ±0.72.3± ±0.72.3± ±0.72.3± IMR Baseline, (U) ± ± ± ± ± ± IS Baseline, % ± ± ± ± ± ± Baseline Angiographic and Clinical Characteristics

Results: 1. Infarct Size: p<0.001

Results: 2. Index of microvascular resistance (IMR):

p = Results: 3. Coronary Flow Reserve (CFR):

Baseline (n =35)Follow-up (n= 35)P Infarct size, % <0.001 Index of microvascular resistance <0.001 Coronary Flow Reserve LVESV (ml) LVEDV (ml) LVEF (%) Results: Temporal changes (from baseline to 5-months follow-up) in all parameters which were used in the study [microvascular perfusion parameters, infarct size and Left ventricular volumes and function] :

CFR Group 1 (n =17)Group 2 (n=12)P Change in infarct size, % Change in LVESV, % Change in LVEDV, % Change in LVEF, % IMR Group 1 (n= 11)Group 2 (n=18)P Change in infarct size, % Change in LVESV, % Change in LVEDV, % Change in LVEF, % Comparisons of the relative changes in infarct size, left ventricular volumes and ejection fraction from baseline to long term follow-up between the two groups which were constituted according to mean values of relative changes in CFR and IMR. Group 1: In whom percent change in improvement in CFR or IMR from baseline to 5 months follow-up were below the mean value; Group 2: In whom percent change in improvement in CFR or IMR from baseline to 5 months follow-up were above the mean value. Sezer, M. et al. Circ Cardiovasc Interv 2010;3:

Comparisons of temporal changes in IS between 4 days and 5 months between the 2 groups, which were constituted according to the mean value of relative change in IMR (-33%) and CFR (41%) from baseline to 5-month follow-up Sezer, M. et al. Circ Cardiovasc Interv 2010;3:

Correlations between microvascular perfusion parameters and infarct size: The IMR, measured at two days after pPCI, correlated with 4 th day (r= 0.40, p= 0.01) and 5 th month IS (r= 0.44, p= 0.007). Relationship between early-phase IMR and 5 th month IS was still significant even after controlling for early IS (r= 0.36, p=0.03). The CFR, measured at early post-AMI phase, correlated with long term IS (r= 0.40, p= 0.009). But, there was no correlation between CFR and early infarct size. Correlation between early phase CFR and 5th month IS remained significant after controlling of early-phase IS (r= 0.35, p= 0.04).

βp Baseline infarct size 0.6<0.001 IMR CFR Predictors of 5 months infarct size

βp Change in IMR Change in CFR Predictors of the relative change in infarct size

Sezer, M. et al. Circ Cardiovasc Interv 2010;3: Correlation between relative improvements in CFR and IS from baseline to long-term follow-up

Correlation between relative improvements in IMR and IS from baseline to long-term follow-up Sezer, M. et al. Circ Cardiovasc Interv 2010;3:

Conclusions: The findings of the present study are threefold: 1. In patients with STEMI who underwent primary PCI with stenting and experienced no events during 5-month follow-up, the microvascular function in the IRA territory significantly improved. 2.This improvement of microvascular function was proportionally associated with a reduced infarct size and improved left ventricular function at follow-up. 3.The microvascular function parameters measured early after STEMI independently predicted the infarct size at follow-up.

These findings indicate that: 1. There is a strong connection between microvascular and infarct remodeling processes after reperfused STEMI. 2. Integrity and functionality of the microcirculation at the territory of the IRA is the main determinant of the evolution of infarct size. 3. Infarct size reduction is proportional to microvascular functional improvement in the long- term.

Therefore, therapeutic approaches including prevention of microvasculature during acute phase, and stimulation of reconstitution of microcirculation during follow-up may help to achieve further myocardial healing in STEMI patients.