The main findings of this study include: 1) HLI, dysglycemia, high NLR, and anemia were independently associated with the risk of 1-year mortality after primary PCI in patients with STEMI and 2) addition of these blood biomarkers to the TIMI risk score for STEMI significantly improved the discriminatory performance. To our knowledge, this is the first study to report that integrating blood biomarkers routinely measured in the emergency room with a conventional risk score incrementally improves the accuracy of 1-year mortality prediction in STEMI.
Many biomarkers are routinely measured at the time of presentation to monitor the general health status of a patient, including liver function, glucose metabolism, presence of anemia, or inflammation status. These biomarkers are not commonly used for risk stratification in STEMI. In addition, conventional risk scoring systems for STEMI do not include routinely measured biomarkers as predictors, except for serum creatinine or hemoglobin. Previous studies have revealed that many biomarkers, such as serum transaminases, glucose, or NLR, are independently associated with poor outcomes in STEMI [3, 5, 6, 9, 13, 14]. However, there is little data that comprehensively evaluates the prognostic impacts of routinely measured blood biomarkers and the incremental value of combining these with a conventional risk score. In this respect, our model, which adds four predictors (HLI, dysglycemia, high NLR, and anemia) determined from routine blood tests on admission to an established TIMI risk score, had a substantial incremental impact on the discriminatory power. In particular, our combined model improved risk reclassification in patients without mortality, suggesting a more accurate capacity to reliably identify patients with low risk for mortality. This may help to select low-risk patients for early hospital discharge. A study of a prospective cohort, consisting of nearly 2000 MI patients, reported that adding several routine biomarkers returned a significantly better prediction of mortality or recurrent MI within 6 months than the GRACE risk score [15]. This study used 9 biomarkers as continuous variables, including urea, sodium, potassium, alkaline phosphatase, low-density lipoprotein cholesterol, glucose, hemoglobin, and C-reactive protein. It is difficult in practice to apply an additional biomarker as a continuous variable to a conventional risk scoring system at the bedside. Therefore, we divided biomarkers into binary variables, according to cut-off values that were previously determined or statistically calculated. This is a more practical approach for risk stratification at the time of presentation, without the aid of a computer.
It has been previously reported that each individual component of our risk model is significantly related with a high risk of adverse events. Recently, there have been a few reports stating the independent association between serum transaminases and cardiovascular outcomes in patients with STEMI [5, 16, 17]. The HLI, defined as increase in serum transaminases more than two times the upper limit of normal, was associated with high risk of mortality and major adverse cardiovascular events after primary PCI in STEMI [5]. Of note, Moon, et al. reported that HLI was closely correlated with left ventricular systolic dysfunction after PCI [5]. Furthermore, admission and peak levels of serum transaminases were significantly related with infarct size, left ventricular ejection fraction, and the presence of microvascular damage in a study using cardiac magnetic resonance imaging [17]. The presence of HLI on admission may be a very sensitive marker suggesting significant left ventricular systolic dysfunction before primary PCI.
Previous studies have described the relationship between hyperglycemia on admission and poor outcomes in acute MI, regardless of the diabetic status [13, 18]. Hyperglycemia might aggravate organ damage by inflammation, endothelial dysfunction, increasing oxidative stress, and coagulation [19–21]. Hypoglycemia on admission has also been related to higher mortality, suggesting a U-shaped relationship between glucose levels and poor prognosis [14]. A plausible mechanism is that hypoglycemia increases the risk of arrhythmia, through changes in autonomic activity and effects on repolarization [22]. Our group also reported that dysglycemia with the same definition as that of the present study, was an independent predictor of in-hospital death in STEMI [6].
Anemia is associated with an increased risk for morbidity and mortality in acute MI [3, 9]. Anemia can potentially worsen myocardial ischemic insult by decreasing the oxygen content of blood delivered to the stressed heart and increasing myocardial oxygen demand and cardiac output for adequate systemic oxygen perfusion [23, 24]. Anemic patients have a higher prevalence of baseline comorbidities and receive less guideline-based pharmacological treatments and reperfusion therapy than non-anemic patients [25]. Anemia on admission is also associated with an increased risk of contrast-induced nephropathy after primary PCI [26]. Among the established risk scoring models in STEMI, only the CADILLAC (the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) risk score includes anemia as a predictor of mortality [27].
Finally, the NLR has recently emerged as a potential prognostic biomarker for various cardiovascular diseases [7, 8]. A high NLR has been associated with an increased risk of short- and long-term mortality after primary PCI in patients with STEMI.[28, 29] The NLR is an indicator of systemic inflammation, which plays a role in the repair and remodeling of infarcted heart tissue [30]. A high NLR (> 4.25) could predict adverse left ventricular remodeling 6 months after anterior STEMI [31]. Among patients with acute MI who underwent PCI, a high post-PCI NLR was related with the extent of myocardial infarction, as measured by cardiac magnetic resonance imaging [4]. In the present study, the best cut-off value of NLR to predict 1-year mortality was 4.3, which was consistent with that in previous studies [28, 29]. A high NLR was the most powerful predictor of 1-year mortality among the biomarkers routinely measured in blood tests.
The combination of HLI, anemia, dysglycemia, and NLR may represent an additional biochemical marker for indicating the severity and extent of myocardial damage, as well as the presence of adverse cardiac remodeling. This information can enhance other conventional risk predictors, such as clinical presentation, left ventricular systolic function, and atherosclerotic burden. The information on HLI, anemia, dysglycemia and NLR is typically taken from the very first routine blood test at the time of presentation, even before PCI. They are readily available and not costly. Thus, our study suggests that the combination of HLI, anemia, dysglycemia, and NLR with a traditional risk score model may provide valuable information for very early risk stratification in patients with STEMI undergoing primary PCI.
There are several limitations in this study. First, as an observational study, it is possible that residual confounding factors not adjusted by multivariate analysis were partially responsible for the present findings. Second, it is not conclusive that elevated serum transaminases were solely associated with hypoxic liver damage. In addition, the cut-off value of HLI have not been fully verified. Third, we had to calculate the best cut-off value of NLR, which may raise statistical inaccuracy. Finally, we did not externally validate our findings. Further studies are required to validate our findings externally and prospectively.