Early predictors of left ventricular function improvement late after myocardial infarction

Background/Aim. Prognosis after acute myocardial infarction (AIM) depends on the extent of irreversibly damaged myocardium and viable tissue due to stunning or hibernation. The aim of the study was to assess the prognostic significance of early echocardiographic parameters of myocardial viability in prediction of late recovery of regional and global ventricular function. Methods. The study prospectively included 40 patients after the first, uncomplicated univessel AIM treated with percutaneous coronary intervention (PCI). Low-dose dobutamine echocardiography (LDDE) was preformed 7–10 days after AIM and follow-up resting echocardiography from 7 to 12 months later. Results. The sensitivity and specificity for the prediction of post revascularisation regional, dyssynergy improvement were 61.29% and 94.59% respectively. The positive and negative predicative values were 90.48% and 74.47% respectively. The number of viable segments (p = 0.01) and extent of contractile reserve (p = 0.01) were univariate, independent predictors of improvement in ejection fraction (EF). From the multivariate stepwise regression analysis contractile reserve was selected as most powerful predictor of late recovery of left ventricular contractile function (p = 0.007). Receiving-operator characteristic curve (ROC) analysis demonstrated that three or more recovered segments were necessary for an improvement of left ventricular ejection fraction (LVEF) ≥ 5% after the revascularisation, with the highest sensitivity, 100% and specificity 56% (p = 0.01). Conclusion. Low-dose dobutamine echocardiography is a powerful predictor of the regional dyssynergy recovery late after AIM treated with PTCA with implantation stent. Late full functional improvement of the left ventricle is related to the extent of contractile reserve and amount of viable tissue. At least three recovered segments are necessary for a significant recovery of the global left ventricular contractility.


Background
It is well known that prognosis after myocardial infarction (IM) depends on the extent of ventricular damage and on residual ventricular function 1,2 .However, impaired ventricular function in patients with coronary artery disease may be due to a permanent, fixed scar resulting from myocardial necrosis, or to the presence of dysfunctional but viable myocardium, either "stunned" 3 or "hibernating" 4 .However, dysfunctional but viable myocardium may recover function if blood flow is restored [5][6][7] .It is conceivable that in patients with ventricular dysfunction related to acute myocardial infarction revascularization would improve ventricular function and, consequently, prognosis.Percutaneous transluminal coronary angioplasty (PTCA) with systematic stenting is regarded as ideal primary treatment for acute myocardial infarction with ST elevation.Clinical outcome and recovery of myocardial contractility after a successful reperfusion are determined with the transmural extent of necrosis, the amount of viable tissue and patency of infarcted coronary artery 8 .
Low-dose dobutamine stress echocardiography may reliably identify a viable but non-contractile myocardium early after acute myocardial infarction and predict a reversible dysfunction 7,9,10 .To our knowledge, there are a limited number of studies that were carried out to estimate the relation between acute phase and predischarge echocardiographic predictors on late improvement in contractility.The present study was undertaken to assess the prognostic significance of early echocardiographic parameters of myocardial viability and contractility in prediction of late recovery of regional and global ventricular function.

Methods
We prospectively enrolled 40 consecutive patients admitted for the first, uncomplicated, single vessel acute myocardial infarction.The diagnosis of IM was based on the typical ischaemic chest pain, acute ST segment elevation in two or more leads, and the characteristic increase of serum cardio-specific enzymes.We excluded patients with left main or multivessel disease, severe valvular heart diseases, previous myocardial infarction and an idiopathic dilated cardiomyopathy.Low-dose dobutamine echocardiography (LDDE) was performed to all the patients from 7 to 10 days after an acute coronary event.All the patients were successfully treated by PTCA with or without stenting within twelve hours after the onset of symptoms.Initial TIMI (Thrombolysis in Myocardial Infraction) flow grades of 0, 1, 2 and 3 were found in 30 (75.0%), 0 (0%), 5 (12.5%), and 5 (12.5%) patients, respectively.After percutaneous coronary interventions (PCI), TIMI flow grade 3 was visualized in 31 (77.5%) and TIMI flow grade 2 in 9 (22.5%)patients.
Two-dimensional transthoracic echocardiograms were performed in the standard views and 12-lead electrocardiogram was recorded with the patients at rest.Dobutamine was infused through an antecubital vein at dosages of 5 μg•kg - 1 •min -1 , for 5 minutes at each dose.Subsequently, two other steps were added (with 10 μg•kg -1 •min -1 and 15 μg•kg -1 •min -1 ), echocardiogram was monitored during each stage.In addition, blood pressure, heart rate and 12-lead electrocardiogram were followed during every step of test.Semiquantitative analysis of wall thickening and inward motion of the endocardium was performed using the classical 16-segment model 11 .Regional wall motion abnormality of each segment was assessed using a four-point scoring system: 1 = normal wall thickening; 2 = hypokinesia; 3 = akinesia; 4 = dyskinesia.Regional dyssynergy was defined when a score ≥ 2 was assigned to a myocardial segment in two different echocardiographic views.For each segment, viable myocardium was considered to be present when at any stage of the dobutamine administration the score of the segment decreased by at least one grade -i.e. the improvement of wall thickening from hypokinesis to normal, or from a dyskinesis to hypokinesis or to normal (improvement from dyskinesis to akinesis was not considered as marker of viability).
During follow-up to assess the regional and global functional outcome of contractile function of left ventricle, control resting echocardiography was obtained in all the patients after 7 to 12 months.
Control echocardiograms were compared with the corresponding rest image obtained in the acute stage for comparative segmental analysis; recovery was defined as a normalization of wall motion and thickening in the affected area.We also assessed functional outcome of global contractile function of the left ventricle through procentual improvement of ejection fraction (EF).

Statistical analysis
The continuous data were expressed as mean±standard deviation.The differences between the data were analyzed by independent samples Student's t-test.Event frequency between the two groups of revascularized patients, with or without viable myocardium, was analyzed by the χ 2 test (McNemar test for paired proportions).Sensitivity, specificity, positive and negative predicative values of dobutamine echocardiography for predicting recovery of regional dyssinergy was calculated using standard definitions.The relative EF procentual recovery was counted as EFbas-EFcont/EFbas•100%. Univariate linear regression analyses were used to examine the predicative power of each single variables of LDDE preformed early after acute event (i.e.number of viable segments, wall motion score index -WMSI) regarding the procentual increase in EF after a follow-up period.Stepwise multiple logistic regression analyses were used to identify the most powerful independent predictors regarding the procentual increase in EF after a follow-up period.Bivariate correlation was used to determine the relation between the number of recovered segments and improvement in EF.The number of recovered segments requaired for a clinically significant improvement of EF was determined by receiving-operator characteristic curve (ROC) analysis.The optimal cut-off value was the number of segments that yielded the highest sum of sensitivity and specificity.A probability p = 0.05 was considered to be statistically significant.The SPSS statistical package (SPSS 10.01 for Windows, SPSS Inc, Chicago, Illinois) was used for analysis.

Results
The mean age of patients was 62.0±12.11years.There were 27 man and 13 women.Clinical characteristics and angiographic data, and biochemical status of the population are listed in Table 1.The mean to time percutaneous coronary intervention (PCI) was 5.09±3.80hours.During a follow-up period two of 40 patients (5%) died due to sudden cardiac death, 23 patients (57.5%) experienced new non-fatal cardiac events (defined as a recurrent episodes of angina pectoris or arrhythmias).
No significant side effects, symptoms, or complications were observed during LDDE and the mean global wall motion score index at peak dose was 1.37±0.26.The mean numbers of viable and non-viable respestively segments were 3.15±2.50and 2.35±2.99.An average value of registrated contractile reserve (changes of WMSI from baseline to peak) was 0.23±0.25 (Table 2).The mean control echocardiographic EF was 44.00±9.06%,and the mean global wall motion score index was 1.50±0.31.After revascularisation, an average relative improvement in EF was 9.71±15.75%.At control echocardiography functional significant recovery of global contractile function of the left ventricle, improvement of EF larger than 5% was noted in 24 of 40 patients (60%) (Table 2).
In order to assess diagnostic value of LDDE in prediction of regional improvement in the revascularised patients early after IM, we considered 15 patients without any occurrences of new cardiac events during the follow-up pe- segments.An improvement of function also was observed in 2 of 37 non-viable segments, whereas in the remaining 35 necrotic segments no change in function could be observed.The sensitivity and the specificity for the prediction of post revascularisation regional improvement of segmental wall motion by LDDE were 61.29% and 94.59%, respectively.Positive and negative predicative value of LDDE were 90.48% and 74.47% respectively.On the basis of linear univariate regression analysis, two echocardiographic variables were selected as independent predictors of late functional recovery of global contractile function of the left ventricle, which are listed in Table 3.
From the multivariate stepwise regression analysis as contractile was selected the most powerful independent predictor of late recovery of left ventricular contractile function reserve what was verified during low dobutamine infusion (Beta-0.44,t-2.89, p=0.007) (Figure 1).The relation between the numbers of dysfunctional segments that improved in contractile function after revascularization and the change in EF are shown in Figure 2 (p = 0.02, r = 0.43).ROC analysis demonstrated that three or more recovered segments were necessary for an improvement of ≥ 5% in EF after revascularisation.This value of three improved segments had the highest sensitivity and specificity (100% and 56%, respectively) to predict improvement of EF (Area 91%, p = 0.01).

Discussion
Until today, many studies have confirmed that dysfunctional, viable myocardium can recover function if blood flow is restored.Therefore, early recanalisation of infarcted coronary artery may improve ventricular function and consecutively prognosis.The present study was carried out to assess the prognostic value of early LDDE in the prediction of improvement of regional and global left ventricular contractile function in the infarcted patients treated with PCI.
During our study we detected the sensitivity and specificity for the prediction of post revascularisation regional improvement of segmental wall motion by LDDE 61.29% and 94.59%, respectively.Positive predicative and negative predicative values of LDDE were 90.48% and 74.47%, respectively.Metaanalysis of seven studies confirmed the ability of LDDE to predict recovery of regional function after acute myocardial infarction.These studies involved 291 patients studied 3 to 12 days after acute myocardial infarction with follow-up evaluations to reassess ventricular function 4 weeks to 9 months later.Overall, the sensitivity for detecting reversible regional dysfunction has ranged from 66-86%, with specificities ranging from 68-94%.The overall positive predicative accuracy of low dose dobutamine in these studies has averaged 71%, with a negative predicative accuracy of 87% 9,[12][13][14][15][16][17] .

Number of recovered
Leclercq et al. 18 found similar results in 40 patients with acute myocardial infarction with primary angioplasty.Sensitivity, specificity, positive and negative predictive value of dobutamine echocardiography in predicting improvement in contractile function at the follow-up were 82, 83, 78, and 86%, respectively.
Our results demonstrated somewhat lesser value of the sensitivity that may be in relation with the higher number of akinetic (3.58±2.55)comparing with hypokinetic (1.58±2.47)segments, in an average number of all (5.43±2.71)dysfunctional segments.
Our observation is in concordance with several authors who reported that the sensitivity of low dose dobutamine echocardiography in prediction of improvement in regional function might depend on the severity of baseline wall motion abnormalities.The sensitivity for predicting recovery of function based on the presence of inotropic reserve was higher in hypokinetic than in akinetic regions.The reported sensitivities for akinetic regions ranged from 74 to as low as 35% 14,15,17 .Leclercq et al. 18 also confirmed this finding while they were comparing positive predictive value between hypokinetic and akinetic segments, which was significantly higher in hypokinetic segments (73% vs. 21%; p < 0.05).
Other authors emphasized that there was a complex relation between viability and contractility with a spectrum of contractile dysfunction related not only to the balance between necrosis and viability but also to the extent of metabolic damage in viable myocytes.So previous, severe histological and biochemical changes, developed mainly due to repetitive stunning, may be responsible for delayed recovery of the function beyond a 7-to 12-month-period in which this study was preformed 12,15,19 .
From a clinical point of view, improvement of the global left ventricular function is more important than recovery of regional function.Increase in global left ventricular EF is one of the main determinants of survival in patients after acute myocardial infarction treated with PCI.The response to revascularisation is also determined with a number of non-echocardiographic variables, including the adequacy of revascularisation of target vessels, the overall status of the ventricle (very large ventricles are unlikely to recover dramatically), and the extent of scar tissue (thinned tissue is unlikely to recover).We tried to define early echocardiographic predictors of global contractile function recovery.
The present study shows that the improvement of the global left ventricular function between 7 and 12 months after the primary stenting for AMI is independently correlated to the extent of viability expressed by the number of viable segments and residual contractile reserve registrated during LDDE.The contractile recovery was related to a higher number of viable segements and to a greater contractile reserve.Some authors analyzed 41 patients with a single vessel disease and successful primary stenting for the first acute myocardial infarction with 201Tl single photon emission computed tomography, contrast ventriculography, and intracoronary Doppler performed 7 days after the primary stenting.The detected myocardial viability was independently correlated to the contractile recovery after 6 months 20 .
In a study with patients reperfused with the primary coronary angioplasty contractile reserve detected by LDDE 1-4 days after IM was also associated with recovery of the global contractile function at the follow-up 18 .
Lancellotti et al. 21in a group of patients reperfused with thrombolytic therapy found that contractile reserve was independent predictor of full recovery of contractile function late after acute myocardial infarction.Similar results were confirmed in a pooled analysis of the currently available dates from Schinkel et al. 22 .
Extensive viable myocardium has also been associated with with preservation of the left ventricular size and reducing of left ventricule remodeling 8,23 .
In addition, other authors presented results, which emphasized the prognostic importance of revascularisation of hibernating myocardium, verified almost a direct impact of detected viability and contractile reserve on late functional recovery 20,21,24,25 .
Previous studies showed that a substantial amount of jeopardized myocardium needs to be present to result in an improvement of EF after revascularization.Several authors represented different observations in revascularised patients with ischemic left ventricule, demonstrating that an improvement in EF after revascularization had been associated with 4 or more dysfunctional but viable segments on LDDE 26, 27 , while others that 3 or more segments were predicative with full recovery of the global contractile ventricular function 28 .
The present study demonstrates that three or more improved segments are needed for full recovery of EF after revascularization (≥ 5%).The obvious discrepancy between the previous studies and the present study may be due to different populations that were observed during the investigation and to a different diagnostic accuracy of viability testing.We also have to think about different techniques used for revascularisaton, and about periprocedural necrosis of viable segments that may occur.
However, this study has some limitations: the study observed a small number of patients, coronary angiographies were not repeated at the one-year-follow-up in our study, and, therefore, reocclusion or restenosis can not be definitively excluded, and quantitative measurements of the left ventricular volumes were not obtained, so we were not able to determine impact of viable myocardium on left ventricle remodeling.Finally, we followed-up our patients from 7 to 12 months, but it can not be excluded that functional improvement may occur beyond this period.Because of that, the follow-up of this study is needed.

Conclusion
Low-dose dobutamine echocardiography is a powerful predictor of the recovery of regional dysfunction late after myocardial infarction treated with PCI.Late full functional improvement of the left ventricle is related to the presence of contractile reserve and the amount of viable tissue.At least 3 recovered segments are necessary for functional significant recovery of the global contractility (improvement of left ventricular EF ≥ 5%).