Biomaker evaluation for major adverse cardiovascular event development in patients undergoing cardiac Surgery

Introduction

Cardiac surgery (CS) is a major surgery associated with substantial morbidity and mortality [1]. Despite improvements in anesthesiology, surgical procedures and postoperative care, cardiovascular complications still represent an important cause of postoperative morbidity and mortality [2]. Thus, the occurrence of major adverse cardiovascular events (MACE) as a complication after major surgery is not infrequent [3]. The definition of MACE involves several of those cardiovascular complications: acute myocardial infarction, stroke, heart failure, and also mortality itself after a cardiovascular procedure [4].

Several risk factors, such as age, gender, and comorbidities, have been used to assess the risk of MACE in patients who undergo surgery. However, MACE is not just a consequence of these risk factors or preexisting comorbidities, many intraoperative variables may influence the development of postoperative complications, and therefore MACE development [5]. The inflammatory response that occurs as a consequence of an intense surgical procedure and prolonged cardiopulmonary bypass might play a key role in the development of adverse cardiovascular events after CS, emphasizing the close relationship between inflammation and outcomes [6], [7]. Some biomarkers may have a potential role in MACE prediction: cardiac biomarkers such as high-sensitive troponin I or T (hs-TnI/T) have been demonstrated to be stronger predictors of adverse cardiovascular outcomes [8], whereas some inflammatory biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6), have a controversial association with MACE although it seems that there may be a strong rationale [9], [10], [11], [12], [13].

Most recently, immature platelet fraction (IPF), also called reticulated platelets, has been gained interest as a potential predictor of MACE after surgery [5], [14], [15]. They are metabolically and enzymatically more active than mature platelets and have a greater prothrombotic activity, which is closely related with decompensated inflammatory status [16]. In addition, IPF has recently shown an association between inflammatory response and outcomes after CS [17]. In consequence, it seems likely that IPF may be associated with MACE after CS. The usefulness of the IPF is based on the fact that its measurement has been currently integrated into the routine hematology analyzer, making the IPF value available in a generalized way.

In agreement with previous data we hypothesized that the cardiac and inflammatory biomarkers could be associated with the development of cardiovascular outcome and mortality after CS. Therefore, our study was aimed to evaluate the association between postoperative biomarkers, such as hs-TnT, CRP, PCT, IL-6, and IPF with MACE development in the setting of CS.

Materials and methods

Results

During the study period, 210 adult patients (n=120) were included. Demographics and preoperative data of all patients and grouped according to MACE development are shown in Table 1.

The median ICU stay was 3 (2–5) days and the mean APACHE II was 12.9 ± 4.6. At least one outcome event of the MACE definition was diagnosed in 31 (14.8%) patients (Table 2). More than one outcome was occurred in five patients. Two patients showed heart failure (HF) and death. One patient developed HF and myocardial infraction (MI) and another patient presented HF and stroke. Finally, the last patient presented HF, MI, and death.

The most frequent surgery was single-valve surgery (n=83; 38%), followed by CABG (n=72; 34%), mixed procedures (CABG plus valve: n=22; 10.5%), double valve (n=17; 8%), aortic surgery (n=11; 5.3%), and miscellaneous, which mainly included myxoma extraction (n=5; 2.4%). The remaining surgical parameters are shown in Table 3.

Discussion

Despite surgical advances and improvements in the postoperative management of CS patients, cardiovascular complications after CS are an important issue that can worsen patients’ outcomes. In this prospective study, with more than 200 patients who underwent CS, we found that the delta of IPF, and the delta of hs-TnT to a lesser extent, are both associated with postoperative MACE development, independently of the presence of established risk factors.

Our findings may demonstrate the potential usefulness of IPF and hs-TnT to detect increased risk of MACE development after CS. This result was in concordance with previous studies. Multiples studies have shown the association of hs-TnI/T with MACE [26], [27], [28]. To date, only one published study found a relationship between IPF and MACE, but this study was performed in non-CS patients [5]. To the best of our knowledge, there is no study showing this association in CS patients until now.

CS may exacerbate or enhance the inflammatory response, which has important clinical implications leading to postoperative heart failure. Many biochemical and molecular mechanisms are involved in the pathogenesis of the inflammatory response: nitric oxid alteration generation, increased levels of proinflammatory cytokines, and endothelium dysfunction, among others. As a consequence, the inflammatory response after CS may increase the risk of a postoperative cardiac event as well a variety of organs dysfunction [29].

Since an inflammatory response could be involved in the pathogenesis of cardiovascular outcomes after CS, we hypothesized that inflammatory biomarkers such as PCT, CRP, IL-6, and IPF could be associated with MACE development.

As expected, on the one hand, we found that some laboratory parameters related with renal, hepatic, and also leukocytes, are higher during postoperative period in patients who developed MACE compared to those who did not. MACE is closely linked with inflammatory response. Likewise, this inflammatory response contributes to the pathogenesis of organ failure [29].

On the other hand, in our study, we found that at least one of the criteria of MACE was present in 31 patients. No differences were found between types of surgical procedures and MACE development. Regarding biomarkers, all studied biomarkers demonstrated higher values in the MACE group, with statistically significant differences in delta values for PCT, hs-TnT, and IPF. No differences between groups were found for the deltas of IL-6 and CRP. It is well-known that PCT, IL-6, CRP, and also IPF are strongly related with infections; hence, we also examined the results after excluding patients who developed an infection during the first 3 days after surgery.

The behavior of the deltas of different biomarkers were the same even after excluding patients with early postoperative infections. Regarding IL-6, a recent study performed in adult CS found a significant association with IL-6 levels and mortality following CS [30]. In contrast with our study, they studied 1-year mortality.

Despite differences in CRP, the delta not being statistically significant, its behavior showed the same trend (positive) in both groups. CRP results were lower at ICU admission compared to CRP levels 24 h after surgery, which may be related to the kinetics of this acute-phase protein. Early postoperative CRP levels start to increase within 2 h and achieve their peak after 48 h [31].

A major surgical procedure always triggers a significant inflammatory response, and CRP increases after CS as a response to inflammation induced by surgery trauma in an unspecific way, which may ultimately explain why we did not find differences between groups. CRP does not represent a useful biomarker in this setting because of its elevation after an uncomplicated course.

Some studies have reported higher PCT levels in patients with complications after CS. Liu et al. [32] found a PCT peak within 24 h postoperatively, noting that PCT concentrations and PCT clearance were significantly higher in the non-survivor group compared with survivor group after CS. Clementi et al. [13] found that PCT concentrations measured at 48 h after CS were significantly higher in renal and respiratory outcomes and in septic patients, and in agreement with our study, they did not find differences in cardiovascular outcomes either between patients who died during hospitalization, at 30 days or at 6 months.

Troponin T or I are cardiac biomarkers that reflect the pathophysiological mechanism of MACE from a direct myocardial injury point of view. In a large cohort of coronary artery disease patients, elevated hs-TnI levels were associated with an increased risk of MACE [8]. Another study conducted by Mauermann et al. [26] examined the association of troponin changes from first and second postoperative days in CS patients with all-cause mortality and cardiac morbidity, finding that an increase of more than 10% in troponin levels was significant associated with the endpoint. All these findings are in accordance with our study, which were found even after cross-clamping time multivariate analysis adjustment.

Research on IPF has recently focused on the potential association with clinical outcomes in patients with cardiovascular diseases and major surgery. While IPF production is known to be promoted by low platelet concentration in blood, its role in inflammatory conditions is still less understood and the mechanism for increased IPF levels after surgery have not been well explored so far. Growing evidence supports the fact that the pathophysiological mechanism through which IPF increases after inflammatory stimuli is related with thrombopoietin regulation in response to acute-phase mediators. IL-6 increases thrombopoietin transcription from the liver and consequently thrombopoietin rises causing a reactive platelet production [33].

Previous studies demonstrated the association of IPF with inflammatory response complications but only one of these was performed in CS patients [17]. IPF levels may be useful as a biomarker for the early identification of patients at risk of inflammatory response development after CS. The role of IPF in infection has been widely studied. Previous research revealed its utility especially in septic patients. Park et al. [34] found that IPF has high sensitivity and accuracy in the discrimination of septic from nonseptic patients. Moreover, Koyama et al. [35] reported that immature platelet count is associated with major mortality in septic patients. However, publications regarding IPF association with complications after surgery are scarce. Our data are in agreement with a study performed by Anetsberger et al. [5]. These authors found that high postoperative IPF levels are associated with an increased risk of major adverse cardiovascular as well as thromboembolic events in patients who underwent non-CS.

Conclusions

In summary, increased levels of the deltas of IPF and hs-TnT between 0 h and at 24 h after CS were associated with worse clinical outcomes related with adverse cardiovascular events during ICU stay and mortality at 30 days in our population. Our research shows that the deltas of IPF and hs-TnT remain associated with MACE development even after intraoperative factor adjustment, such as cross-clumping time and transfusion of hemoderivatives. Our data suggest that IPF and troponin postoperative measurement would be helpful for MACE assessment in patients undergoing CS. These data are of potential interest as IPF is an easily and inexpensively obtained routine laboratory test that is readily incorporated into clinical practice.