1Acute Coronary Disease Unit, Heart Institute (InCor), University of São Paulo Medical School, Av. Enéas de Carvalho de Aguiar, 44, 2nd Floor, 05403000, São Paulo, Brazil
2Magnetic Resonance Imaging Sector, Heart Institute (InCor), University of São Paulo Medical School, Brazil
3Nuclear Medicine Sector, Heart Institute (InCor), University of São Paulo Medical School, Brazil
4Echocardiography Sector, Heart Institute (InCor), University of São Paulo Medical School, Brazil
5Catheterization Laboratory, Heart Institute (InCor), University of São Paulo Medical School, Brazil
6Electrocardiology Sector, Heart Institute (InCor), University of São Paulo Medical School, Brazil
7Acute Coronary Heart Institute (InCor), University of São Paulo Medical School, Brazil
Received December 10, 2003; revised August 26, 2004; accepted September 3, 2004 * Corresponding author. Tel: +55 11 30695058; fax: +55 11 30883809. E-mail address: joaoclima{at}uol.com.br
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Abstract |
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Methods and results Thirty-six patients with occluded infarct-related artery between 12 h and 14 days post-anterior MI were randomized to percutaneous coronary intervention (PCI group) or conservative therapy (no-PCI group). Magnetic resonance imaging was performed at enrolment and after 6 months. The left ventricle was divided into infarct, adjacent, and remote segments. There was no difference in relation to LV volume between groups at the 6 month follow-up. Change in LV ejection fraction was favourable to the PCI group: 5.00% vs. 0.76%, P=0.012. Change in circumferential shortening (Ecc) of the remote segments in the PCI group was significantly better than in the no-PCI group: 1.67±6.30% vs. 0.29±6.02%, P<0.001. Infarct size and LV mass were similar between groups.
Conclusions Late recanalization improved LV ejection fraction and myocardial contractility in late follow-up, but did not change the ventricular volumes. Improvement in the left ventricle global and regional contractility may benefit the long-term outcome in post-MI patients with sustained patency of the infarct-related artery.
Key Words: Ventricular remodelling Myocardial function Myocardial contractility Late coronary recanalization
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Introduction |
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On the other hand, the potential mechanisms of benefit attributable to late patent IRA are not associated with preservation of cardiac function, but improvement in myocardial healing, lesser infarct expansion, and reduction of electrical instability, as demonstrated in experimental trials.4,5 A disproportionate improvement in survival, when compared with improvement in ejection fraction (EF) alone, has been observed in clinical studies of thrombolytic therapy,6,7 and is cited in support of a beneficial role of late recanalization by other mechanisms, independently of myocardial salvage.
Small randomized studies811 assessed the role of angioplasty in late reperfusion and those data regarding LV remodelling are not uniform, due, at least in part, to limitations inherent to the imaging methods utilized.
The present study analysed the role of late recanalization on LV remodelling by magnetic resonance imaging (MRI), using specific techniques to evaluate regional contractility (myocardial tagging)12,13 and myocardial viability (myocardial delayed enhancement).14
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Methods |
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Thirty-six patients were enrolled from June 1999 to July 2001; from these, 30 underwent two MRI studies (enrolment and 6 month follow-up) and were analysed in this study. Of the remaining six patients, four were not submitted to MRI due to technical difficulties and two died during follow-up. The causes of death determined at autopsy were anterior wall LV rupture and massive pulmonary embolism.
Coronary angiography
Coronary angiography (Integris H-3000, Philips Medical Systems, The Netherlands) was performed between 12 h and 14 days after MI using standard techniques. It was recorded in multiple angulated projections in order to visualize the IRA. Collateral circulation was analysed according to Schwartz et al.15
Myocardial perfusion scintigraphy
Myocardial perfusion scintigraphy (General Medical Electric Systems, DST, Sophycamera, Buc Cedex, France) with 201Tl (IPEN, São Paulo, Brazil) plus dypiridamole (Behringer Ingelheim, Willich, Germany) was performed in all patients after coronary angiography. The LV anterior wall was evaluated in relation to ischaemia and viability through redistribution and reinjection images at enrolment and 6 months later using standard techniques.
MRI methods
MRI studies were performed in a 1.5 T (General Medical Electric Systems, SIGNA, CV/I, Waukesha, MN, USA) magnet using a cardiac phased-array surface coil.
The cardiac images were obtained during breath-hold of 1215 cardiac beats (1015 s on average) at the end of the expiration, using synchronization with the electrocardiogram. Three specific pulse sequences were used: cine-MRI with FIESTA technique (Fast Imaging Employing Steady Technique Acquisition), cine-MRI with myocardial tagging, and myocardial delayed enhancement.
Initially, the first images were acquired to evaluate the correct position of the cardiac coil and to define the short and long axis view of the left ventricle. Eight to 12 short-axis slices were acquired with 8 mm thickness and 2 mm interval, in order to cover the LV from apex to base. The long axis was perpendicular to the short axis, in a radial form, with a 45° interval. All the short-axis and long-axis slices were acquired with all the pulse sequences described below.
The first pulse sequence, the FIESTA technique, was performed to evaluate end-diastolic volume (EDV), end-systolic volume (ESV), and EF using the following parameters: FOV (field of view) 3438 cm; matrix 256x128; receiver bandwidth 125 kHz; k-space segmented 812 lines; TR 3.9 ms; TE 1.4 ms; flip angle 45°; 3/4 FOV; number of excitations equal to 1 and 20 phases for each cardiac cycle.
We acquired images using myocardial tissue tagging in order to evaluate regional contractility. The pulse sequence used a modified DANTE/SPAMM technique16 to obtain the tag lines with the following parameters: FOV 3438 cm; matrix 256x128; receiver bandwidth 31.2 kHz; k-space segmented 810 lines; 6.7 TR ms; TE 3.2 ms; flip angle 15°; 3/4 FOV; number of excitations equal to one and number of phases for each cardiac cycle equal to 20. The tag lines were adjusted to 7 mm of distance and had 12 pixels of width. Short-axis images were acquired with grid tag lines at 45 and 135° in relation to phase direction.
Patients received an intravenous bolus of 0.2 mmol/kg of gadolinium (Omniscan®, Amersham Health, Cork, Ireland). Ten to twenty minutes after gadolinium injection, images were acquired using the myocardial delayed enhancement technique, which is a gradient-echo pulse sequence with a preparatory pulse of inversion-recovery. The parameters utilized were: TR 7.2 ms, TE 3.2 ms; matrix 256x192; flip angle 20°; width 31.2 kHz; and time of the inversion (TI) 150250 ms; number of excitations equal to two and acquisition in every heartbeat (1 RR). We adjusted the inversion time to null the signal from normal myocardium after contrast. Normal myocardium presents a null signal (dark myocardium) while the infarcted region appears intensely white with clear distinction between them.
Image analysis
The calculation of LV mass, EDV, ESV and EF was based on endocardial and epicardial contours of all short-axis slices at end-diastole and end-systole using the software Mass Analysis Plus® (Leiden University Medical Center and MEDISMedical Imaging Systems, Netherlands). Simpson's method was applied to calculate LV volumes and mass. The end-systolic and end-diastolic phases were defined on a short-axis at the mid portion of the left ventricle, visually as the ones with smaller and greater LV cavity, respectively. These end-systolic and diastolic phases were used for all short-axis slices from apex to base.
For myocardial tagging analysis we used the Findtags software (Johns Hopkins University, Baltimore, MD, USA), which tracks the tag lines semi-automatically, calculates the displacement field, and depicts the movement of any myocardium point in the same plane.
The orthogonal displacement generated by the grid of myocardial tagging in the LV short axis, provides a field of two-dimensional displacement used to describe the true motion of myocardial points during ventricular contraction. With this tool, we calculated the circumferential shortening (Ecc) and the normal strain to compare myocardial regional contractility between infarcted, adjacent, and remote segments using a six-segment model in each short-axis slice and only one transmural layer. Therefore, each myocardial segment corresponds to one value of Ecc. The Ecc value is expressed as a negative number, so that the more negative, the greater the shortening and therefore, the higher the contraction. Additionally, for visualization only, colour maps displaying the regional distribution of Ecc were superimposed on each short-axis slice tagged image at all cardiac phases, allowing for a dynamic visualization of Ecc changes during the cardiac cycle.
Myocardial viability was analysed quantitatively by planimetry [National Institutes of Health (NIH) image software, Bethesda, MD, USA] of the areas with increased signal intensity in relation to the normal myocardium, in each segment, and in all of the left ventricle, using the myocardial delayed enhancement technique. The infarct size was expressed as a percentage of total LV mass.
Infarcted segments were defined as segments containing any portion of enhanced myocardium. The adjacent segments were defined as the segments immediately neighbouring the infarcted segments, with no myocardial hyper-enhancement. The remote segments were defined as segments not in contact with infarcted segments.
Randomization
Patients with an occluded IRA (TIMI flow grade 0 or 1) without collateral circulation in the distribution of the IRA, or with collateral circulation but no evidence of myocardial ischaemia or significant viability evaluated by myocardial perfusion scintigraphy, were randomized to either recanalization by percutaneous coronary intervention (PCI) with stent in addition to medical therapy (PCI group), or medical therapy alone (no-PCI group).
Percutaneous coronary intervention
PCI was attempted using standard techniques. Selection of guide wires, balloons, inflation pressures, stent size, and use of adjunctive therapies were left to the discretion of the operator. A stent was deployed in all patients of the PCI group and dilated with standard clinical practice to ensure full strut expansion. Success defined as TIMI flow grade 2 or 3 and residual stenosis <50% at the culprit coronary artery was achieved in all cases.
Medical treatment after randomization
During and after MI, the patients were treated according to the current guidelines,17 mainly with (i) aspirin; (ii) beta-blockers; (iii) ACE-I; and (iv) lipid-lowering agents. In addition, the patients with stents received clopidogrel for 30 days post-procedure. Other cardioactive agents were administered at the discretion of the attending physician.
Six month follow-up
Patients were kept under observation for 6 months with regard to cardiac events including cardiac death, recurrent non-fatal MI, angina, and the development of congestive heart failure.
Sample size calculations
LV remodelling has emerged as one of the most important predictors of long-term survival after MI.18 Two prospective randomized trials examining the open artery hypothesis have reported serial changes in ESV.8,10 The following considerations were taken into account to calculate the sample size: (i) the LV volume change to achieve normality; (ii) a mean percentage change of 20% of ESV in the no-PCI group at 6 months; (iii) expected standard deviation equal to 15% for both groups; (iv) alpha=0.05; and (v) power=80%. The sample size was estimated according to mean percentage change in the PCI group using the STPLAN statistical program (University of Texas, Houston, TX, USA): for a mean percentage change in the PCI group equal to 0% the sample size estimate would be 20 patients and for a mean percentage change equal to 5% the sample size would be 34 patients.
Statistical analysis
Data were analysed using SigmaStat 2.0 [Jandel Corporation (http://www.systat.com/products/SigmaStat/?sec=1000)] and STATA 6.0 software [Public Health Medicine at GKT School of Medicine (http://www.stata.com/support/quest/)].
Qualitative variables were presented as absolute number (n) and relative (%). Fisher's exact test or 2 testing were used appropriately to compare the groups.
Results of normally distributed, continuous variables were expressed as the mean value±SD and continuous variables with a non-normal distribution were presented as a median value and interquartile range. Verification of normal distribution of data was accomplished using the KolmogorovSmirnov test. Changes from baseline in EDV, ESV, and EF were normally distributed in the two groups and changes from baseline in infarcted, adjacent, and remote segments had non-normal distribution. Differences between groups were assessed by unpaired Student's t test or MannWhitney U test as appropriate.
Repeated measures analysis of variance (ANOVA) was used to compare the means at baseline and 6 month follow-up between groups and to adjust for the non-independence of measures (circumferential shortening, %Ecc) in infarcted, adjacent, and remote segments. The sources of variation were: group (two levels), region (three levels), time (two repeated measures); the interactions between group, region, and time; subjects (30 levels for patients) and the error. The post hoc comparisons between the means were performed using the Tukey HDS-test. A P-value <0.05 (two-tailed) was considered statistically significant.
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Results |
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LV size and function
There was no difference between groups in relation to LV volumes during the 6-month follow-up: EDV change: 2.02±13.63 mL/m2 versus 7.19±14.89 mL/m2, P= 0.335 and ESV change: 1.40±8.28 mL/m2 versus 5.02±12.73 mL/m2, P=0.105, respectively, in the PCI and no-PCI groups. The change in EF showed an improvement in the PCI group: 5.00±5.09% and a deterioration in the no-PCI group one: 0.76±6.63% P=0.012 (Figure 1).
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Clinical events
During the 6 month follow-up there were four clinical events in the no-PCI group (22.22%) and none (0%) in the PCI group. One patient needed hospitalization due to heart failure; another had heart failure refractory to clinical treatment at the end of follow-up (this patient had a large LV aneurysm demonstrated at the 6-month follow-up by MRI and was corrected by surgery). Two other patients died; the causes of death were anterior wall LV rupture and massive pulmonary embolism. By using Fisher's exact test it can be seen that such differences between the groups are not statistically relevant (P=0.114).
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Discussion |
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The open artery hypothesis has shown conflicting results in humans. Two small studies done with PCI without stent both presented neutral results.8,9 In the TOMIIS study,9 however, a subgroup analysis showed that patients with a patent culprit coronary artery 4 months after PCI (n=12) had a significant improvement in EF, in comparison with patients with an occluded artery (n=25), similar to our results.
The TOAT study11 found a worse LV dilatation by echocardiography, in the PCI group, in comparison with no-PCI. The authors pointed out that these results could be related to the occurrence of micro-embolization to the microvasculature in the PCI group, reducing the perfusion and resulting in adverse ventricular remodelling. However, the biochemical markers of myocardial necrosis were not measured routinely, making the evidence of this possibility less obvious. An alternative explanation for these negative results could be related to restenosis and reocclusion rates that were higher than expected, with a subsequent high rate of late events, as observed in the PCI group.
Contrary to the previous study, Horie et al.10 found a significantly lesser LV dilatation in the PCI group, relative to the no-PCI group, after the 6 month follow-up.
The DECOPI study,23 the largest randomized trial, with 212 patients, showed improvement of LV function at 6 month follow-up in accordance with the findings of the current study. Although there was a slightly lower mortality rate in the intervention arm, the DECOPI study23 did not show significant differences in the primary endpoint after an average of 34 months of follow-up. Additionally, the DECOPI study did not show a worse remodelling in the angioplasty arm as was seen in the TOAT study.11
At least in part, the conflicting results among the studies could be explained by differences in protocol. For instance, Pfisterer et al.24 reported significant attenuation of LV dilatation in patients undergoing intervention 23 weeks after MI, but not in patients undergoing the same procedure 3 months later. In the TOAT study,11 the mean time to recanalization was 26±18 days, while in the study of Horie et al.10 the mean time was 8.29±9.68 days and there was a median time of 8 days in the DECOPI study.23 Our study was the first one to utilize myocardial perfusion scintigraphy in order to rule out ischaemia before randomization and the mean time to recanalization was 8.34±3.25 days. With regard to myocardial contractility, a significant improvement in the adjacent and remote segments was detected in the PCI group, relative to the no-PCI group, suggesting that late recanalization can be useful in this setting.
The possibility of an improvement related to a previous depressed myocardium that may occur after a reperfusion25,26 does not seem to be the case, at least in the infarcted and remote area, where at baseline similar contractility patterns were demonstrated for both groups.
The improvement in the contractility beyond the infarcted area in the PCI group, especially in the remote segments, emphasizes the fact that remodelling occurs in the ventricle globally, and that adaptive responses involving non-infarct adjacent and remote myocardium help preserve stroke volume. This improvement can be associated with a lesser rate of apoptosis in the area of infarct and remote regions, as demonstrated by Abbate et al.27 in a necropsy study. Finally, the findings of contractility on the remote segments in the no-PCI group, could be related to collagen deposition beyond the area of infarct, as suggested by Sun et al.28
Study limitations
Our study has some limitations. First, a second angiogram was not performed at the end of follow-up, which prevented knowledge of the patency of the IRA in both groups at that time point. Second, the small sample size and perhaps the relatively short duration of follow-up may have influenced the ability to detect differences between groups. Third, the two groups differed with regard to the use of clopidogrel for the first 30 days, which may provide benefits independently from recanalization. Finally, taking into account the relatively small sample size and the highly selected patients included in the study, our findings cannot be applied to the general MI population.
Clinical implications
Clinical benefits of IRA recanalization later than 12 h post-MI remain unclear. Nevertheless, in our study, late intervention after MI demonstrated a beneficial effect on myocardial contractility, EF and a favourable trend in ESV in late follow-up. These results concur with observational data where sustained IRA patency after MI confers long-term benefits, and support the development of new studies in order to answer the question definitively.
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Conclusion |
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Acknowledgements |
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References |
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