Article Text
Abstract
Background Mortality derived from ST-elevation myocardial infarction (STEMI) has decreased due to primary percutaneous coronary intervention (PCI). Paradoxically, the incidence of heart failure secondary to left ventricular remodelling (LVR) is on the rise due to the survival derived from reperfusion strategies. The aim of this study was to assess the prognostic value for LVR of biomarkers involved in several pathophysiological mechanisms activated during STEMI treated with primary PCI.
Methods 112 patients with STEMI undergoing primary PCI were evaluated. LVR was defined as a ≥20% increase in the left ventricular end-diastolic volume at 6-month follow-up assessed using echocardiogram as compared with that at discharge. Blood samples were obtained for glucose, N-terminal pro-brain natriuretic peptide, troponin T (TnT), matrix metalloproteinase 9, procollagen type-I N-terminal propeptide and high-sensitivity C reactive protein (hs-CRP).
Results 24 patients (21%) developed LVR. Higher levels of maximum TnT, and matrix metalloproteinase 9 and hs-CRP at discharge, were detected as independent risk factors for LVR (OR 1.310, p=0.03; OR 1001, p=0.04; OR 1.040, p=0.04, respectively). Both TnT and hs-CRP showed significant ability to distinguish patients who developed LVR from those who did not, being the values that yielded the greatest sensitivity and specificity as follows: TnT 7.0 μg/l (73%, 84%), hs-CRP 30 mg/l (59%, 85%).
Conclusions Myocardial necrosis, as measured by released TnT, and inflammation state evident due to circulating levels of CRP are factors that may play a major role in the development of LVR following STEMI treated with primary PCI.
- Biomarkers
- left ventricular remodelling
- ST-elevation myocardial infarction
- cardiac remodelling
- haemodynamics
- three-dimensional
- MRI
- cardiomyopathy hypertrophic
- aorta
- great vessels and trauma
- cardiac function
- genetics
- heart failure
- myocardial disease
- echocardiography
- coagulation factors
- deep vein thrombosis
- platelet activation
- transient ischaemic attack
- congenital heart disease
- tissue doppler
- myocarditis
- stress
- transoesophageal
- transthoracic
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- Biomarkers
- left ventricular remodelling
- ST-elevation myocardial infarction
- cardiac remodelling
- haemodynamics
- three-dimensional
- MRI
- cardiomyopathy hypertrophic
- aorta
- great vessels and trauma
- cardiac function
- genetics
- heart failure
- myocardial disease
- echocardiography
- coagulation factors
- deep vein thrombosis
- platelet activation
- transient ischaemic attack
- congenital heart disease
- tissue doppler
- myocarditis
- stress
- transoesophageal
- transthoracic
Introduction
Two major complications of ST-elevation myocardial infarction (STEMI) are heart failure and death.1 ,2 Over the past few decades, this scenario has experienced a decrease in mortality rates due to both primary percutaneous coronary intervention (PCI) and thrombolysis.3 ,4 However, the incidence of heart failure is on the rise due to, paradoxically, the prolonged survival derived from management of STEMI by reperfusion strategies.5 ,6 From the onset of STEMI, genome expression, molecular, cellular and interstitial changes take place and are clinically manifested as changes in size, shape and function of the left ventricle.7 This chain of events, referred to as left ventricular remodelling (LVR),7 is a largely demonstrated predictor for heart failure and cardiovascular death beyond the acute phase of STEMI.8
Before LVR becomes evident, several pathophysiological mechanisms are initiated during the acute–subacute phase of STEMI: (1) hyperglycaemic stress;9 (2) myocardial necrosis;10 (3) imbalances between synthesis and degradation of extracellular matrix;11 ,12 (4) inflammation state secondary to gene expression of cytokines;13 (5) cardiac wall stress and myocardial stretching.14 Biomarkers representing these biological pathways are now becoming recognised as influential in subsequent LVR development. The aim of this study was to assess the prognostic value to predict LVR in patients treated with primary PCI, by multiple biomarkers that represent several pathophysiological mechanisms activated in STEMI.
Material and methods
The study was conducted in a tertiary care hospital with round-the-clock primary PCI service. Patients undergoing primary PCI were prospectively and consecutively enrolled for a period of 11 months. The study protocol was approved by the institutional review board, and informed consent was obtained from all participants.
Study population
Eligibility for primary PCI was based on the presence of typical acute chest pain and persistent ST-elevation (≥30 min, and either >1 mm in ≥2 contiguous limb leads or >2 mm in ≥2 contiguous precordial leads). Criteria for exclusion included: impossibility of determining the culprit lesion, unsuccessful primary PCI (residual stenosis >30% in the culprit lesion and/or thrombolysis in myocardial infarction flow <3), presence of other significant cardiac condition (valvulopathy, cardiomyopathy or pericardial disease) or non-related heart conditions with estimated life expectancy <12 months, known malignancy, inflammatory or collagen disorder and ongoing infectious disease. A total of 164 primary PCIs were performed, although 155 were considered successful. Eight of these patients died during their hospital course and 147 were discharged. Within the next 6 months, a number of events limited the completion of the study protocol in 16 patients: sudden death (1) reinfarction (5) coronary restenosis (7) and coronary disease progression (3). Out of the remaining 131 patients, 14 belonged to other hospital areas and the final echocardiogram was not available from them, and 5 refused follow-up. The resulting population being part of the study consisted of 112 patients.
Echocardiographic study
All subjects had two transthoracic echocardiograms, at discharge and at 6 months after the index event. Both studies were performed using the commercially available ultrasound scanner iE33 (Philips; Andover, Massachusetts, USA). They first included standard 2D and Doppler acquisitions; subsequently, 1–2 intravenous bolus (0.5 ml) of contrast agent (SonoVue® (Rovi; Madrid, Spain)) were injected and videoclips from the apical 4- and 2-chamber views were stored to determine by the biplane method of discs, left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV), and ejection fraction. According to previous methodology,15 LVR was defined as a ≥20% increase in EDV at 6-month follow-up assessed using echocardiogram as compared with that at discharge.
Use of contrast agent was aimed at optimising delimitation of endocardial boundaries and minimising measurement variability of ventricular volumes. The first echocardiogram was performed at discharge, once having overcome the acute phase of myocardial infarction (days after event: median 6 days, interquartile interval 4–12 days). For both echocardiograms, contrast was used in clinically and haemodynamically stable settings, with close symptomatic and electrocardiographic monitoring.
An experienced echocardiographer, blinded to biomarker results, performed off-line processing of the acquired datasets. The first 15 cases were reanalysed by the same investigator (at least 8 weeks later), and by another experienced echocardiographer to test intra- and inter-observer variability for EDV and ESV determinations.
Biomarker testing
At enrolment, together with primary PCI, blood samples for glucose and N-terminal pro-brain natriuretic peptide (NT-proBNP) were collected. Serial measurements of troponin T (TnT) were performed: on admission, at 0–3, 6, 12 and 24 h after primary PCI, and daily thereafter until discharge; extra determinations might have existed and relied on the discretion of the corresponding physician. Eventually, the maximum TnT value was considered for analysis. At discharge, and coinciding with the first echocardiogram, blood samples were drawn for NT-proBNP, matrix metalloproteinase 9 (MMP-9), procollagen type-I N-terminal propeptide (PINP) and high-sensitivity C reactive protein (hs-CRP).
Venous blood was collected into gelified Serum Clot Activator—Vacuette (Greiner Bio-One) tubes, which were immediately transferred to a central laboratory. Processing included centrifugation at 3000 g (15 min, 4°C) and storage at −70°C. Glucose levels were determined by hexokinase method; electrochemiluminiscence immunoassay was performed for analysis of NT-proBNP, TnT and PINP (Elecsys proBNP, TnT fourth-generation assay, and Elecsys tP1NP, respectively; Roche Diagnostics; Basel, Switzerland); MMP-9 determination was performed by enzyme immunoassay (Human MMP-9 Platinum ELISA; Bender MedSystems GmbH; Vienna, Austria); and hs-CRP by latex particle-enhanced immunoturbidimetric test (Tina-quant CRP (latex) HS; Roche Diagnostics; Basel, Switzerland). Minimum sensitivity and upper limit of detection were 2–750 mg/dl for glucose, 5–35 000 pg/ml for NT-proBNP, 0.01–25 μg/l for TnT, 5–1200 μg/l for PINP, 8–100 ng/ml for MMP-9 and 0.1–20 mg/l for hs-CRP; values higher than the upper limit of detection were automatically diluted for each biomarker (manually diluted for MMP-9). The highest intra- and inter-assay coefficients of variation were 0.7% and 1.2% for glucose, 1.3% and 4.6% for NT-proBNP, 2.0% and 6.2% for TnT, 1.9% and 4.8% for PINP, 7.3% and 10.2% for MMP-9, and 0.4% and 3.5% for hs-CRP. The 99th percentile of the TnT immunoassay for 1951 healthy volunteers was <0.01 μg/l, with a recommended diagnostic threshold of 0.01 ng/l (lower limit of detection) for spontaneous acute myocardial infarction.
Statistical analysis
The Kolmogorov–Smirnov and Shapiro–Wilk tests were used to analyse normality within continuous variables; all of them (except age) were found to deviate from a normal distribution. Therefore, they are expressed as medians and IQR (age as mean±SD) and comparisons between groups were performed using the Mann–Whitney U test. Categorical variables are expressed as frequencies and percentages, and comparisons were performed using either Pearson chi-square or Fisher exact tests, as appropriate. The ORs and 95% CIs investigating the independent predictive role of biomarkers for LVR were assessed by logistic regression. Variables with p<0.2 in univariate analysis were entered into a final multivariate model, which was adjusted by those clinical, procedural and echocardiographic variables considered relevant. The ability of these parameters to discriminate patients who developed LVR from those who did not was evaluated by receiver-operating characteristic (ROC) curve analysis. The optimal cut-off value was defined as the point providing the greatest sum of sensitivity and specificity. Statistical significance was defined as a value of p<0.05. Intra- and inter-observer variabilities were calculated as the absolute difference of the corresponding pair of repeated EDV and ESV determinations expressed as percentage of their mean.
Results
Biomarkers from 112 patients were eventually available. The mean age was 60±11 years, predominating male gender (86%). LVR was observed in 24 patients (21%), whose mean per cent change in EDV from baseline to 6-month echocardiogram was 22%. The reproducibility analysis of left ventricular volumes was as follows: intra-observer variability EDV 5% and ESV 4%; inter-observer variability, EDV 9% and ESV 12%. The baseline and procedural characteristics of the study population are summarised in table 1.
Comparisons regarding body surface area-indexed EDV and ESV at discharge yielded no differences between LVR and non-LVR groups (figure 1A). However, while patients who did not develop LVR showed no increase in both volumes at 6 months, LVR patients had marked increases; as a result, their EDV and ESV were significantly higher than those from the non-LVR group (median (IQR) EDV: 69 (23) ml/m2 vs 55 (17) ml/m2, p<0.001; median (IQR) ESV: 32 (24) ml/m2 vs 21 (10) ml/m2, p<0.001). On the other hand, the echocardiographic studies were able to relate lower ejection fraction at discharge to detection of LVR at 6 months (median (IQR) ejection fraction: 50 (17)% vs 59 (14)%, p=0.02) (figure 1B).
The predictive value of biomarkers for LVR was evaluated after univariate logistic regression (table 2), which highlighted TnT, MMP-9, NT-proBNP at discharge and hs-CRP as candidates for multivariate analysis. Higher serum levels of TnT, MMP-9 and hs-CRP remained as independent risk factors for LVR, even following adjusted analysis by ischaemic time, location of culprit lesion within left anterior descending artery and ejection fraction at discharge (table 3). In the ROC curve analysis, TnT and hs-CRP demonstrated areas under the curve of 0.801 and 0.741, respectively, with significant ability to distinguish patients who developed LVR from those who did not (figure 2).
Discussion
LVR begins rapidly following STEMI, and although the initial remodelling phase may be considered beneficial,7 progressive postinfarction left ventricular dilation is an important predictor of mortality.8 Thus, the search for a greater understanding of the biological pathways initiated at a molecular level, and the study of the factors which might predict LVR represent a relevant issue of investigation. This study, focused on the analysis of biomarkers during the acute–subacute phase of STEMI treated with primary PCI, emphasises the significance of myocardial necrosis as measured by released TnT, and inflammation state evident due to circulating levels of CRP, as factors that may play a major role in the subsequent development of LVR.
Several studies have shown that on admission, hyperglycaemia in patients with myocardial infarction is an important predictor of short- and long-term adverse events.16–21 In our study, patients who developed LVR were not found to have significantly greater levels than those without LVR. This needs to be addressed within the context of both specific type of acute coronary syndrome and therapeutic approach. Thus, most prognostic data in this setting come from studies without stratification according to the presence or not of ST-segment elevation.16–21 On the other hand, more recent data from STEMI patients raise further controversy: (1) studies where primary PCI was the main reperfusion therapy show that even though hyperglycaemia is associated with poor prognosis, this is confined to short-term events22 or non-clinical surrogate variables;23–25 (2) primary PCI (vs thrombolysis) seems to balance the greater mortality associated with hyperglycaemia;26 (3) while a larger infarct size may be present among patients with hyperglycaemia, this fact might not relate to a higher mortality.27 Despite the fact that our study might be in keeping with these previous observations, a significant increase in EDV has been reported elsewhere in patients with anterior myocardial infarction showing stress hyperglycaemia on admission.28 However, data from that study differ from the present work regarding the single location of infarct and that a majority of patients underwent thrombolysis, facts likely related to a greater LVR rate (31%) observed by these investigators; the primary PCI-based reperfusion strategy employed in our series, and a lower incidence of LVR (21%) might partly explain the lack of association between an elevated glycaemia and LVR. Moreover, the above mentioned study only included non-diabetic patients,28 which should also be taken into consideration, since it has been suggested that patients without diabetes showing stress hyperglycaemia on admission for myocardial infarction are at increased risk of mortality and congestive heart failure, as compared with diabetic patients.17 Although the prognostic impact of glycaemia on admission seems to be demonstrated in acute coronary syndromes, further investigation is warranted to clearly identify the actual underlying mechanisms participating in this association.29
In our series, as has been shown by others,30 patients who suffered LVR had higher levels of NT-proBNP at discharge, whereas this biomarker was near normal on admission, with no difference between groups. It seems that the appropriate time to determine NT-proBNP with a greater predictive power for death or ventricular dysfunction is not on admission, but a few days following infarction.31 However, levels of NT-proBNP at discharge did not remain as an independent predictor in the model adjusted by variables whose preponderance has been shown to be related to larger infarct size (maximum TnT, culprit lesion within left anterior descending artery, and ischaemic time). These findings may be explained because during the acute phase of STEMI, NT-proBNP release is due to myocardial dysfunction and mainly due to ischaemia.32 ,33 In fact, this ischaemic setting might result in either myocardial necrosis, or stunned viable myocardium where wall function recovery is likely to exert an antiremodelling effect.34 Furthermore, recent data have shown the role that mid-regional pro-adrenomedullin, another biomarker whose release is also stimulated by both cardiac pressure and volume overload, might play over natriuretic peptides in predicting outcome in patients with heart failure after myocardial infarction.35
Alteration in collagen turnover within the infarcted myocardium is thought to be a significant pathway leading to LVR. This process involves collagen synthesis and degradation. Synthesis can be assessed by measurement of circulating collagen fragments, and thus, both levels of PINP and procollagen type-III N-terminal propeptide have been found to show changes in their concentrations following myocardial infarction.36 In the present study, PINP was chosen because it represents around 65% of total collagen synthesised in relation to coronary artery disease as compared with approximately one-third for type-III propeptide.37 However, no relationship was found between PINP levels and LVR, in accordance with findings by other investigators.11 Conversely, although certain association of PINP with clinical outcomes has been reported elsewhere,38 this biomarker did not show independent predictive value when C-terminal telopeptide of type I collagen, which reflects collagen type I degradation, was considered. On the other hand, degradation of extracellular matrix relies on MMPs, with particular importance of MMP-9 and MMP-2, which are found elevated after myocardial infarction. In the present study, MMP-9 was considered as a representative marker of this pathway based on the results of previous studies where it showed a better association with LVR and heart failure than that for MMP-2.39 ,40 Our findings supports the independent role that the former plays in this process; however, MMP-9 lacked in significant power for discrimination between patients developing or not developing LVR (figure 2), which is likely to indicate the need to consider the involvement of several components in this pathway.12 ,41
Cardiac troponin release is a specific marker of myocyte injury, and its measurement during the acute phase of myocardial infarction reflects to some extent the size of infarcted area,10 which is among the most clearly identified risk factors for LVR.42 Although some investigators have reported no role of acute-phase troponin levels for predicting LVR, this finding may have an explanation in the inclusion of only cases featuring anterior wall myocardial infarction.43 Thus, other publications have shown that location of myocardial infarction in the anterior wall is independently associated with higher peak troponin levels.10 Our study, which included all location STEMIs, detected maximum TnT as an independent determinant of LVR; this finding might be in keeping with previous studies where its measurement in the acute phase of myocardial infarction has a relevant role in prediction of heart failure and adverse cardiovascular events at long-term follow-up.10 ,44 Along with TnT, the inflammatory response following myocardial infarction might represent a cornerstone of the pathophysiological tissue repair leading to LVR.13 CRP, an acute-phase reactant released by stimulation of upstream cytokines (such as interleukin 6, with which CRP keeps a high correlation in the release pattern after myocardial infarction45), reflects the degree of this inflammatory response,46 ,47 present within the infarcted area and within remote areas far away from the mainly involved territory.47 ,48 Indeed, this extensive presence in the context of myocardial infarction, and its demonstrated participation in complement complex activation put CRP forward as an actual mediator of intense myocardial damage that contributes to postinfarction LVR.46 ,48 On the other hand, although CRP determination in the first 2 days after PCI-reperfused STEMI has been found to show significant predictive value for clinical outcomes,47 ,49 it is known that this biomarker remains increased up to 1–4 weeks after the event.47 ,48 Our study, in which CRP levels were determined by a high-sensitivity method, supports that the measurement at discharge beyond those first 48 h maintains to some extent its usefulness in predicting prognosis, given its independent association with LVR. Lastly, taking together the TnT and hs-CRP optimal cut-off values derived from the analysis of ROC curves, the detection of increased levels in both biomarkers yielded a positive predictive value for LVR of 77%, while levels below those cut-off values showed a negative predictive value of 97% (figure 3).
Surprisingly, among the baseline characteristics, the smoking habit was associated with less LVR development. This smoker's paradox is overall regarded as a confusion factor related to healthier coronary risk profile.50 Our results are in keeping with this hypothesis as we found that the smoking habit related both to younger patients (55±11 vs 65±10 years; p<0.001) and a trend to lower presence of hypertension (35% vs 53%; p=0.07).
Study limitations
Although our findings are from a single centre, we included a cohort with a wide spectrum of STEMI locations according to culprit vessel, and therefore, a significant variety of cardiac damage. Even though single determination of some biomarkers in this work stands for particular or representative points during the acute–subacute phase of STEMI (glucose at admission, NT-proBNP at primary PCI, maximum TnT), timely determination assessed by serial biomarker measurement might yield a better understanding related to LVR development. In the same way, determination of several biomarkers within each pathophysiological pathway might have shown different results; however, given the complexity inherent to the measurement of all biomarkers involved in these processes, our work only included one biomarker representative of each of these pathways. The study protocol assessed a surrogate variable, namely LVR, instead of clinical outcomes for which a greater study size and a longer follow-up might have been necessary. Finally, since diagnosis of LVR was established by the 6-month echocardiogram, patients initially enrolled who presented with new myocardial infarction or died during the 6 months after STEMI were excluded, which limits the extrapolation of results, in terms of prognostic value of the assessed variables, to the real-life evolvement of coronary artery disease. Additionally, the development of LVR was assumed to be related to the index event and thus, new coronary angiography during follow-up to evaluate infarct-related artery patency was not performed; only those patients with clinical indication underwent new catheterisation, and were eventually excluded if they showed restenosis or progression of coronary disease.
References
Footnotes
Funding The Echocardiography Laboratory at Virgen del Rocio University Hospital has received a research grant from the Andalusian Society of Cardiology (Seville, Spain) aimed at the development of this project. The Andalusian Society of Cardiology had no involvement in the collection, analysis or interpretation of data, the writing of the report, nor in the decision to submit the paper for publication.
Competing interests None.
Ethics approval Comite de Etica de la Investigacion de Centro, Virgen del Rocio University Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.