Main findings
This study aimed to evaluate the role of MPO in CRT recipients and its correlation to CRT response. As a main finding, this study revealed that MPO, which is known to be elevated in CHF, decreased significantly in patients who responded to CRT implantation based on objective clinical parameters (NYHA and walking distance) within 90 days after successful device implantation. For patients who did not show any clinical response to CRT, no significant changes in MPO levels were detectable, despite optimal CRT placement. These differences between responders and non-responders were independent of leukocyte count.
Baseline MPO levels differed significantly between those patients with CRT response as opposed to patients not responding to CRT. For this small-study cohort, an MPO level of 242 ng/ml or higher at baseline predicted a response after successful CRT implantation with a sensitivity of 93.5% and a specificity of 71.4%.
A significant correlation between reverse remodeling (improvement of LVEF, p = 0.005) and physical capacity (NYHA improvement, p = 0.042) was shown for MPO, while NT-pro-BNP did not correlate significantly with response to CRT in our cohort.
Significance of MPO levels
Different levels in baseline MPO values in patients with CHF and eligible for CRT presumably reflect distinct types or severity of CHF and structural remodeling in these patients. Beside LVEF, impaired physical activity and NYHA class often only partially describe the severity of CHF without sufficient discrimination. Baseline levels of MPO might be a more objective parameter to sub-stratify the patient population with CHF. Therefore, markedly elevated baseline MPO levels possibly reflect a more advanced stage of CHF.
In contrast, in patients with low MPO levels at baseline, the severity of CHF and structural remodeling may be less pronounced and, therefore, CRT implantation in these patients might be less beneficial although fulfilling CRT implantation criteria [
9,
10].
The role of MPO as a predictor
To distinguish responders from non-responders before CRT implantation, it would be desirable to have additional tools complementing established clinical parameters such as LVEF and LBBB width [
1]. As mentioned before, evaluation of MPO levels seems to be of value for a thorough assessment of CHF severity and potentially predicting CRT response in these patients. This study revealed a significant correlation between MPO levels and CRT response.
However, to use MPO as a predictor for CRT response before implantation in patients with CHF, a cut-off value would have to be identified. Therefore, in this explorative trial with a small single-center cohort, ROC analysis suggested that MPO values of 242 ng/ml or higher predicted a CRT response with a high sensitivity of 93.5% and an acceptable specificity of 71.4%. This analysis showed that MPO was the only significant parameter for CRT response in comparison with NT-pro-BNP and NYHA class. These findings support the hypothesis that MPO could be used as a preimplantation marker to reveal possible non-responders.
Regarding the role of MPO in the etiology of CHF, promoting increased structural remodeling, high MPO levels may predict a better response to CRT indicating advanced oxidative stress [
9,
10,
16]. The role of CRT for a reversed structural remodeling has been proven in the REVERSE trial [
17]. The fact that, in our analysis, MPO correlated with NT-proBNP, a strong parameter for structural remodeling in heart failure, implies that MPO levels decrease because of reverse remodeling under successful CRT.
Considering improvement of myocardial performance due to CRT (increase of LVEF) strongly correlates with decreasing MPO levels in CHF patients, our data imply that this improvement is promoted by anti-inflammatory effects as described before in several studies [
10,
18,
19].
The effect of hemodynamic improvement in CHF patients on MPO levels has been shown in the previous trials with levosimendan, a drug used in the setting of acute heart failure or worsening of CHF. Blood pressure regulation directly affects PMN activation and endothelial MPO deposition [
20]. The positive effects of CRT on hemodynamics in CHF patients possibly lead to a better MPO clearance. Latter might explain the revealed effects in our cohort.
Furthermore, our data show that MPO may be more sensitive as a clinical marker for CRT response than NT-proBNP. Though, it should be acknowledged that multivariate analysis in larger cohorts will have to prove the incremental benefit compared to clinical markers as LVEF and NYHA.
Previous studies with larger populations have shown that additional assessment of MPO to NT-proBNP was able to increase specificity in heart failure patients (74.1% vs. 40.5% with NT-proBNP alone) [
21]. In contrast to earlier studies, we were not able to confirm a decrease of NT-pro-BNP in CRT responders [
8,
22]. Also, in our cohort there was no correlation between CRT response and the course of NT-pro-BNP. This might be explicable by differences between study populations and follow-up duration. Thus, the patient cohort in the study of Lellouche et al. did not include patients with NYHA class < 3 and follow-up was longer than in our cohort [
8]. We assume that MPO is the more sensitive and, therefore, prompt marker because of its direct mechanistical link to improve hemodynamic in CRT patients. Furthermore, in these trials, NT-proBNP has not been proven to be a sufficient preimplant marker for CRT, due to poor sensitivity of 62% [
7,
8].
A previous trial with 44 pts by Sunman et al. also investigating the course of MPO showed that MPO levels decrease after CRT implantation consistent with our data. In this analysis, the investigators could not find significant differences between responders and non-responders at baseline and during follow-up. However, the goal of that study was to correlate MPO and other cardiac biomarkers. There was no investigation of the correlation between clinical parameters and MPO [
12].
The major aspect why MPO suggests being superior to other markers of oxidative stress is that it is mechanistically linked to the development of heart failure. A major driver in this regard seems to be oxidation of endothelial-derived nitric oxide.
In contrast, other markers like MDA and isoprostanes simply reflect the burden of oxidative stress which might have a higher variability, lower organ specificity, and not a direct link to vascular and or myocardial function. Therefore, we believe that MPO with its profound body of evidence for impacting on vascular function is not only marker but potentially mediator of the disease, which makes it such a powerful indicator of changes in LV function [
10]..
Limitations
There are a few limitations to this study that should be mentioned. Our cohort was relatively small. Larger studies are required to identify a valid cut-off value, while our investigation sought to evaluate the hypothesis of MPO as a possible predictor. Furthermore, a multivariate analysis could be performed in a larger cohort to assess the predictive. Presented data and evaluated MPO levels including a cut-off value reflect a single-center experience. For a cut-off value used in wide clinical practice, prospective trials should be performed. However, the patients’ cohort presented here represents a typical population of CRT recipients undergoing guideline-based therapy.