Ageing, impaired myocardial perfusion, and mortality in patients with ST-segment elevation myocardial infarction treated by primary angioplasty

Giuseppe De Luca, Arnoud W.J. van 't Hof, Jan Paul Ottervanger, Jan C.A. Hoorntje, A.T. Marcel Gosselink, Jan-Henk E. Dambrink, Menko-Jan de Boer and Harry Suryapranata*

Department of Cardiology, ISALA Klinieken, Hospital De Weezenlanden, Groot Weezelanden 20, 8011 JW Zwolle, The Netherlands

Received 25 May 2004; revised 15 November 2004; accepted 9 December 2004; online publish-ahead-of-print 28 January 2005.

* Corresponding author. Tel: +31 38 4244229; fax: +31 38 4243083. E-mail address: h.suryapranata{at}diagram-zwolle.nl

See page 634 for the editorial comment on this article (doi:10.1093/eurheartj/ehi217)


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Aims It is still unknown whether impaired myocardial perfusion helps to explain the higher mortality observed with ageing in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary angioplasty.

Methods and results In 1548 consecutive patients with STEMI treated with primary angioplasty, myocardial perfusion was evaluated by myocardial blush grade (MBG) and ST-segment resolution. All clinical and follow-up data were prospectively collected. Advanced age was associated with a significantly higher clinical and angiographic risk profile. We found a linear relationship between increasing age, decreased myocardial perfusion, and higher 1-year mortality. After adjustment for baseline potential confounding variables, increased age was still significantly associated with impaired myocardial blush (MBG 0–1) (P=0.028), and ST-segment resolution (<50%) (P=0.007). At multivariable analysis both age (P<0.0001) and poor myocardial perfusion (P<0.0001) were independent predictors of 1-year mortality.

Conclusion This study shows that impaired reperfusion is an additional determinant of the poor outcome observed with advanced age in patients with STEMI undergoing mechanical revascularization.

Key Words: Primary angioplasty • Perfusion • Ageing • Mortality


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Advanced age is associated with increased mortality in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary angioplasty.15 Although several factors, such as the presence of co-morbidities, more severe coronary artery disease, and impaired left ventricular function, have been demonstrated to be associated with the higher mortality observed in the elderly,3,4 no data have focused on myocardial perfusion, which represents a well-known determinant of survival.6 The aim of the current study was to investigate the relationship between age, myocardial perfusion, and mortality in patients with STEMI treated by primary angioplasty.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Our population is represented by 1548 consecutive patients with STEMI treated by primary angioplasty at our institution between April 1997 and October 2001. Informed consent was obtained from all patients (or from their relatives in the case of the patient's inability) before the angiogram. Our study was approved by the institutional Review Board. All patients received aspirin (500 mg) and heparin (10 000 IU) intravenously before the procedure. Since the benefits of glycoprotein (GP) IIb/IIIa inhibitors have only been proved recently,7 less than 5% of our patients have received this additional therapy.

Coronary angiography was analysed by an independent core lab (DIAGRAM, Zwolle, The Netherlands), blinded to all clinical data and outcome. Myocardial blush grade (MBG) was assessed after primary angioplasty, as previously described:6 Grade 0, no myocardial blush; Grade 1, minimal myocardial blush or contrast density; Grade 2, moderate myocardial blush or contrast density but less than that obtained during angiography of a contra- or ipsilateral non-infarct-related coronary artery; Grade 3, normal myocardial blush or contrast density, comparable with that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery.

Analysis of ST-segment resolution was performed by comparison between baseline and 3-h 12-lead electrocardiograms (ECGs), as previously described.8 ST-segment resolution was defined according to a threshold of 50%.8

Records of patients who visited our outpatient clinic were reviewed. For all other patients, information was obtained from the patient's general physician or by direct telephone interview with the patient. No patient was lost to follow-up.

Statistical analysis
Statistical analysis was performed with the SPSS 10.0 statistical package. Continuous data were expressed as median with 25–75th percentiles and categorical data as percentage. The ANOVA test and the {chi}2 test were appropriately used for continuous and categorical variables, respectively (two-sided tests). A trend analysis was performed as previously described.6 P<0.05 was considered statistically significant.

Logistic regression analysis was performed to calculate the risk of impaired myocardial perfusion related to age, adjusted for baseline confounding characteristics identified by univariate analysis (P<0.05). All variables were entered en bloc. To assess the linearity assumption we included new variables (representing the highest three quartiles vs. the lowest quartile of age) in the regression analysis and plotted the estimated logistic regression coefficients vs. the quartile midpoints of age.8

The difference in event rates between groups during the follow-up period was assessed by the Kaplan–Meier method using the log-rank test. The Cox proportional hazard method was used to evaluate the impact of myocardial perfusion and age on 1-year mortality after correction for potential confounding factors known to be predictors of outcome [sex, diabetes, previous myocardial infarction (MI), infarct location, time-to-treatment, door-to-balloon time, Killip class at presentation, pre- and post-procedural TIMI 3 flow, angiographic evidence of collaterals, multi-vessel disease, angiographic success]. All variables were entered en bloc. The proportional hazard assumption was visually assessed by the use of Kaplan–Meier survival curves.


    Results
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Characteristics of patient population according to age are reported in Table 1. The prevalence of female gender, diabetes, hypertension, previous infarction, Killip class at presentation, multi-vessel disease, late presentation (>4 h), previous cerebrovascular accident (CVA), post-procedural TIMI 3 flow, and angiographic success significantly changed across age. As shown in Figure 1, we found a linear association between age, impaired ST-segment resolution (<50%) (data available in 1072 patients), and impaired myocardial blush (MBG 0–1). No interaction was observed between ageing, perfusion, and infarct location (anterior vs. non-anterior) (P=0.26). Interestingly, the relationship between age and myocardial perfusion persisted even when the analysis was restricted to patients with post-procedural TIMI 3 flow (Figure 1). The rate of MBG 2–3 increased from 0 to 4.8, 35.7, and 87.5% in patients with post-procedural TIMI 0, 1, 2, and 3, respectively (P-trend <0.0001). After adjustment for baseline confounding factors (gender, diabetes, hypertension, previous infarction, Killip class at presentation, ischaemia time, door-to-balloon time, multi-vessel disease, previous CVA) age was still significantly associated with impaired myocardial perfusion (MBG 0–1) [adjusted OR (95% CI): 1.15 (1.01–1.30), P=0.028] and impaired ST-segment resolution (<50%) [adjusted OR (95% CI): 1.2 (1.05–1.37), P=0.007]. The linearity assumption was confirmed by plotting estimated logistic regression coefficients vs. quartile midpoints of age (Figure 2).


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Table 1 Demographic, clinical, and angiographic characteristics according to age
 


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Figure 1 Relationship between age, MBG, and ST-segment resolution in all patients (left panels) and in patients with post-procedural TIMI 3 flow (right panels).

 


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Figure 2 The linearity assumption (upper graph for myocardial blush and lower graph for ST-segment resolution) was visually analysed by plotting the estimated logistic regression coefficients of the highest three quartiles and the mid-point quartiles of age.

 
At 1-year follow-up (available in the whole population), a total of 92 patients (5.9%) had died. As depicted in Figure 3, mortality was significantly affected by age and myocardial perfusion. After correction for baseline clinically relevant confounding factors (sex, diabetes, previous MI, infarct location, time-to-treatment, door-to-balloon time, Killip class at presentation, pre- and post-procedural TIMI 3 flow, angiographic evidence of collaterals, multi-vessel disease, angiographic success), both age [adjusted HR=1.53 (1.24–1.89), P<0.0001] and impaired myocardial blush [adjusted HR=2.63 (1.58–4.39), P<0.0001] were independent predictors of 1-year mortality. As clearly shown in Figure 3, the risk of mortality associated with advanced age and poor perfusion was stable to 1-year follow-up.



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Figure 3 Kaplan–Meier survival curves according to age (upper graph) and myocardial blush (lower graph).

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
The main finding of the present study is that impaired myocardial perfusion is an additional determinant of the poor outcome observed with ageing in STEMI treated by primary angioplasty.

Ageing, myocardial perfusion, and mortality
Despite the improved outcome determined in elderly patients by primary angioplasty in comparison with thrombolysis, the procedural success and the mortality rate remain high in comparison with younger patients.15

The higher mortality rate observed with advanced age is partially accounted for by the presence of co-morbidities (higher prevalence of hypertension, diabetes mellitus, previous stroke, peripheral vascular disease), more severe coronary artery disease, and impaired left ventricular function.4,5 As confirmed by a previous report,5 we found that patients older than 75 years were frequently women, with high rates of diabetes mellitus and heart failure at presentation. However, the role of myocardial perfusion as a potential determinant of prognosis in older patients with STEMI undergoing mechanical reperfusion has largely not been investigated. In fact, at the timing of coronary recanalization, myocardial reperfusion is achieved only in areas with anatomically preserved microvasculature, whereas reflow does not occur in myocardium with extensive microvascular damage.6,9,10

Many experimental data have shown that ageing is associated with more susceptibility to ischaemia-reperfusion injury.1113 In a recent report,14 ageing was not associated with impaired myocardial reperfusion evaluated by ST-segment resolution. In our study we evaluated myocardial perfusion by the use of both ST-segment resolution and myocardial blush. We found that MBG 0–1 and impaired ST-segment resolution were linearly associated with age. The relationship between age and reperfusion was confirmed even after adjustment for baseline confounding factors. The clinical relevance of this finding is supported by the impact of myocardial perfusion on 1-year mortality. These data strongly support the prognostic role of myocardial perfusion in addition to co-morbidities in the explanation of the poor outcome observed with advanced age.4,5

Several factors may explain our results. It has been shown that ageing is associated with impairment of endothelial and microcirculation function.15 Experimental studies have demonstrated that aged hearts exhibit greater accumulation of [Ca2+] during ischaemia and less functional recovery after ischaemia than mature hearts.11 Additional alterations in metabolic pathways make aged hearts less resistant to ischaemia and ischaemic reperfusion injury.12,13 Previous reports showed significant benefits from intracoronary adenosine or verapamil in reducing microvascular reperfusion damage and infarct size, and improving outcome in patients with STEMI undergoing primary angioplasty.16,17

Furthermore, the complex coronary anatomy observed with advanced age4,18 may be associated with a higher incidence of distal embolization, which is a major determinant of post-procedural myocardial perfusion and clinical outcome.19

Additional administration of GP IIb/IIIa inhibitors has been demonstrated to improve myocardial perfusion, particularly in higher risk patients,20 despite no advantages being found in lower risk patients.21 Additional benefits may be expected when early administration is planned.7,22 However, the potential higher rate of intracranial and major bleeding complications in elderly patients, particularly when combined with thrombolysis,23 may counterbalance the benefits in terms of improved myocardial perfusion and mortality. Further benefits would be expected by distal protection and thrombosuction devices.24,25 However, the more complex coronary anatomy commonly observed in elderly patients4,5 may be an obstacle to the extensive use of such devices in these patients.

Limitations
A major limitation of the current study is that in up to 30% of the total population, ST-segment resolution analysis was not available due to missing or inadequate baseline and/or 3-h ECGs.8

No distal protection device or thrombus aspiration system has been used in this series. Only less than 5% of patients received GP IIb/IIIa inhibitors. However, their benefits in mortality are still controversial, particularly in the elderly, in whom data are still lacking.

Furthermore, post-procedural evaluation of myocardial blush may have contributed to the underestimation of myocardial reperfusion, since effective reperfusion may potentially occur later after acute MI, despite mechanical revascularization.26,27

Data on chronic obstructive lung disease, peripheral artery disease, renal function, and prior medical therapy were not available from the majority of patients and were thus not included in the multivariable analysis.


    Conclusions
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
This study shows an association between age, myocardial perfusion, and mortality in patients with STEMI undergoing primary angioplasty. Therefore, additional mechanical and/or pharmacological therapies should be considered to preserve microcirculation and to improve myocardial perfusion, particularly in elderly patients undergoing primary angioplasty for STEMI.


    References
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 References
 

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