Introduction
In patients with ST-segment elevation myocardial infarction (STEMI), primary percutaneously coronary intervention (pPCI) is an effective strategy to reduce the size of myocardial infarction (MI) [
1]. Other well-established determinants of infarct size are long duration of ischemia, left anterior descending (LAD) artery as culprit lesion, and low pre- and post-procedural thrombolysis in myocardial infarction (TIMI) flow [
2]. Identifying more determinants that influence infarct size could further aid in reducing infarct size. Hypercholesterolemia is a well-known risk factor for developing atherosclerosis [
3,
4] and subsequently for the risk of a MI [
5‐
8]. Moreover, it might also be related to the extent of damaged myocardium in the event of a MI [
9‐
12].
An important part of a patient’s treatment and prognosis is determined by the myocardial infarct size.
Myocardial infarct size can be measured with established biomarkers such as creatine kinase (CK) and cardiac troponin T (cTnT). Peak CK levels are as accurate as cTnT in estimating myocardial infarct size in STEMI patients who underwent successful pPCI [
13], and is an established non-invasive measure of infarct size and severity [
14‐
16]. Furthermore, peak CK levels are strongly associated with clinical outcome [
14‐
16]. Myocardial reperfusion injury (MRI) is the term for further injury to the ischemic myocardium which occurs after restoration of blood flow which reduces the beneficial effect of myocardial reperfusion [
17]. It is suggested that approximately 30% of myocardial infarct size is determined by MRI [
17] and although the pathophysiological mechanisms of MRI are not fully elucidated [
17], this might be preventable. Studies in animal models have demonstrated that hypercholesterolemia may aggravate MRI [
9,
10], e.g., by the no-flow phenomenon [
11] or by increased myocardial oxidative stress [
10,
12] and inflammation [
12].
A relation between hypercholesterolemia and infarct size in clinical studies could have important implications and may lead to more advanced therapies like antioxidant therapy and novel lipid-lowering therapy.
So, we hypothesize that high LDL-cholesterol (LDL-c) levels during admission are associated with infarct size in patients with STEMI. Therefore, the aim of this study was to evaluate the association between baseline LDL-c levels and enzymatic infarct size using peak CK in patients with STEMI after pPCI.
Discussion
The purpose of this large cohort study was to assess whether infarct size in patients with STEMI treated with pPCI is determined by pre-existing factors. The primary finding of this study is that higher levels of LDL-c at the time of admission are independently associated with greater infarct size expressed as peak CK level. In addition, anterior infarction, time of ischemia, low pre-procedural TIMI flow, gender, and previous use of aspirin are factors that are related to infarct size in STEMI patients after pPCI.
Further understanding of the variables that affect infarct size in STEMI patients after pPCI can have important implications for patients’ treatment and prognosis. Owing to improvements of diagnosis, therapy, and care, mortality rates of STEMI patients are reduced at the expense of increasing numbers of STEMI patients with heart failure. This makes it essential to understand what factors are associated with infarct size, particularly if these factors are potentially modifiable, as this could lead to the earlier detection and development of advanced therapies.
This study demonstrates that higher LDL-c levels are associated with greater infarct size in STEMI patients treated with pPCI. Besides high LDL-c levels, anterior infarction, time of ischemia, low pre-procedural TIMI flow, and male gender are shown to be associated with larger infarct size. These determinants are well-established risk factors for a larger infarct size which were earlier identified in a pooled analysis of four randomized STEMI trials by Stone et al. [
2]. Since the mechanisms underlying the effect of higher LDL-c levels on infarct size are still unclear, some explanations may be suggested. Our hypothesis is that a higher LDL-c level itself may aggravate MRI. Several studies with animal models reported that hypercholesterolemia could aggravate ischemia/reperfusion injury [
9‐
12,
23], leading to a greater infarct size. Several mechanisms underlying the relation between hypercholesterolemia and increased myocardial reperfusion injury have been proposed; for example, by increased oxidative stress [
10,
23], reduced extent of the cardioprotective effect of HDL-c [
9], activated endoplasmic reticulum stress-mediated apoptosis [
12], or by upregulation of inflammatory processes [
24]. In human patients, exploration of the link between hypercholesterolemia and infarct size is limited [
25‐
27] and moreover these studies were not able to consistently confirm the results from animal studies. Marenzi et al. conducted a prospective cohort study which evaluated the effect of statin therapy on myocardial infarct size assessed with cardiac magnetic resonance (CMR) in patients treated with pPCI for STEMI [
25]. They observed no significant association between infarct size and LDL-c levels at hospital admission. Some studies suggest that ischemic preconditioning is dependent of serum LDL-c levels present at the time of reperfusion [
26,
27]. Ischemic preconditioning is defined by initiating periods of transient myocardial ischemia and reperfusion before the sustained ischemic episode [
27]. Ischemic preconditioning is a form of cardioprotection, and appears to inhibit lethal reperfusion injury [
26,
27]. Kyriakides et al. [
26] tested the hypothesis that hyperlipidemia inhibits the reduction of myocardial ischemia normally observed after repeated balloon inflations during angioplasty. They showed that hyperlipidemia prevents the reduction of myocardial ischemia on repeated balloon inflations during angioplasty. A similar study, performed by Ungi et al. [
27], scrutinized the effect of high serum cholesterol levels on ischemic preconditioning by means of beat-to-beat analysis of ST segments and found that hyperlipidemia accelerates the evolution of myocardial ischemia and delays recovery upon reperfusion.
Aspirin use prior to a MI was associated with smaller infarct size. To our knowledge no earlier studies were able to show this association. Marenzi et al., for example, found no association between prior aspirin use and infarct size determined with CMR [
25]. Their relatively small population may be the reason for the lack association. Furthermore, in the present study most of the patients with an earlier MI were on aspirin therapy, which might explain why the infarct size was smaller in the patients on aspirin therapy. As a result of earlier damage to the myocardium, CK release might be less than in the case of first STEMI.
As it is generally believed that a substantial part of the myocardial infarct size is determined by MRI [
17], several studies were initiated with the aim to identify cardioprotective agents that may reduce irreversible cell damage upon reperfusion [
17,
28]. As a result of its pleiotropic effects [
29], statin treatment prior to primary PCI in MI patients was proposed as a potential agent that could have an effect on reperfusion-induced cell damage; however, this effect is still controversial as they yielded conflicting results. Several hypotheses could explain the potential effect of statin pre-treatment on reperfusion-induced cell damage and consequently on clinical outcome. For example, statins are known to suppress active plaque inflammation [
30,
31], inhibit thrombosis [
32], improve endothelial function [
33], inhibit cell adhesion [
34], and improve microvascular function [
35,
36], all of which contribute to improved clinical outcome after PCI [
37].
In the present study, statin pre-treatment was associated with lower peak CK level in univariate analysis, but vanished after multivariate analysis. Several animal studies demonstrated a beneficial effect of statin therapy on infarct size after reperfusion [
28,
38]; yet, these results could not consistently be reproduced in patients with STEMI [
25,
37,
39,
40]. These conflicting results could be explained by several reasons. First, the right timing of the statin administration prior to STEMI was diverse, but is of importance since it takes 2–5 h for statins to reach an optimal blood level during reperfusion [
41,
42]. Secondly, the intensity of the statin therapy necessary to attenuate the infarct size differed between the studies. An earlier study conducted in pigs showed that pre-treatment with 160 mg of oral rosuvastatin reduced infarct size, whereas 80 mg had no significant effect [
43]. Finally, in STEMI patients’ myocardial ischemic injury might be too severe to be prevented or reduced [
37].
On the other hand, LDL-c level was significantly lower in patients treated with statin before admission than in patients without statin therapy, which may indicate that not statin use but LDL-c level itself is related to infarct size. Further research, with well-conducted randomized trials that address the issues of timing and the intensity of the statin therapy, is needed in STEMI patients to explore the full potential of pre-treatment with statin therapy and other potential cardioprotective agents that can reduce irreversible cell damage upon reperfusion.
As expected, a high incidence of traditional risk factors such as smoking, hypertension, and dyslipidemia was present in this cohort. Elevated LDL-c is an important risk factor for the development of atherosclerosis and subsequent ischemic heart disease [
7], and the association between these risk factors and cardiovascular mortality has been known for decades [
44]. Therefore, identifying high-risk patients before they develop ischemic heart disease is crucial. The results of this study emphasize not only that primary prevention and timely management of patients with high cardiovascular risk profiles have beneficial effects on the development of ischemic heart disease but also that early identification of patients with high LDL-c levels combined with lifestyle changes and optimal medical treatment might lead to an improved prognosis after having developed ischemic heart disease.
Several limitations of the present study should be mentioned. First, since an observational cohort study was conducted, we could not account for undocumented clinical variables which may possibly have influenced the outcomes. Although this study is retrospectively conducted, all patients are treated according to the institutional MISSION! which provides an integrated approach of MI care to optimize treatment. This yielded in a very homogeneous STEMI population which resulted in a very high number of patients being treated according to the guidelines. Secondly, patients with known coronary artery disease or patients with a previous MI were not excluded in our analysis. In this manner, we believed that it reflects a population-based cohort in the best possible way. Thirdly, information about the number of patients either receiving prasugrel of clopidogrel was not available for this study. Theoretically, prasugrel, a more potent antiplatelet drug, could lead to a smaller infarct size. Furthermore, information about statin compliance, intensity of the statin treatment, and treatment duration prior to MI was not available for this study. This could explain the confined association between statin pre-treatment and lower peak CK levels in this study.
Finally, peak CK levels during admission were used as an estimate of infarct size. Peak serum CK levels can be used to estimate infarct size if reperfusion is established rapidly and successfully [
14‐
16] and peak CK is, compared to cardiac magnetic resonance imaging (cMRI), more easily implemented in daily practice and far less expensive. However, cMRI has emerged as a well-established technique for quantifying myocardial infarct size, has been shown to correlate well with clinical outcome, and is the gold standard. Therefore, further studies are warranted to establish the association between cholesterol levels and infarct size on cMRI.