INTRODUCTION

Cardiac remodeling after acute myocardial infarction (MI) is related to the balance between the extent of ischemia, inflammation, and oxidant radicals and the levels of defense systems against these pathological conditions¹-³. Inflammation is not only a local response but it is also a systemic process that follows the elevation of inflammatory mediators. While extremely elevated inflammation or oxidant radicals are associated with adverse cardiac remodeling (AR), elevated defensive systems (anti-inflammatory and antioxidant balance) are associated with reverse or adaptive cardiac remodeling⁴,⁵.

Monocytes, which are the main players of innate immunity, extravasate to inflammatory tissues after the leukocyte recruitment cascade during inflammation⁶. Lipid-loaded macrophages, which are produced due to the activation of monocytes in the area of inflammation, are of critical importance in the inflammatory response⁷. Oxidation of high-density lipoprotein-cholesterol (HDL-C) mainly occurs in inflammatory microenvironments. HDL-C plays a role in suppressing the activation of monocytes and the proliferation and differentiation of monocyte progenitor cells⁸. Thus, accumulation of monocytes and decrease in HDL-C are associated with atherosclerosis and cardiovascular diseases. Recent studies show that the monocyte to HDL-C ratio (MHR), which is an easily calculable measure, may be a new indicator of inflammation⁹. However, we could not find any studies in the literature exploring the relationship between post-MI cardiac remodeling and MHR. MHR was reported to be an important predictor of the slow-flow/no-reflow phenomenon in MI patients¹⁰. The no-reflow phenomenon was a strong predictor of infarct size and early cardiac remodeling¹¹. We assumed that MHR might be an important indicator in cardiac modeling after MI because of the relationship between high monocyte counts and low levels of HDL-C in inflammatory responses. In the present study, we aimed to investigate the prognostic role of MHR at the time of hospital admission in late cardiac remodeling and subsequent 1-year mortality.

METHODS

This study was planned as a multicenter prospective study between June 2015 and June 2020, including Ankara Dr. Nafiz Korez Sincan State Hospital, Ankara Diskapi Training and Research Hospital, Yildirim Beyazit University Atatürk Training and Research Hospital, and Ankara Numune Training and Research Hospital. Assuming an alpha value of 0.05, power of 0.90, and 25% estimated AR rate in line with previous reports¹², the estimated sample size was at least 157 patients in total. The study was performed in accordance with the Declaration of Helsinki and approved by the Ankara Yildirim Beyazit University Faculty of Medicine's Non-Drug Clinical Research Ethics Committee on 24 June 2013 under Decision No. 2013/106. Written informed consent was obtained from all patients.

This research received financial support from the Ministry of Health of the Republic of Turkey (Department of Research, Development, and Health Technology Evaluation) through project 2015/SAGEM-2/001.

RESULTS

A total of 231 patients were included in the CMR imaging analysis. The mean age was 53.9 ± 8.7 years and patients were mostly male (88.7%) with a representative risk profile for cardiovascular disease. At 6 months post-MI, 20 patients (23.8%) exhibited AR. The median cardiac troponin I (57 ng/L vs. 46.5 ng/L, p = 0.035), median white blood cell count (11.6 × 10⁹/L vs. 10.4 × 10⁹/L, p = 0.038), mean monocyte count (0.8 ± 0.2 × 10⁹/L vs. 0.7 ± 0.2 × 10⁹/L, p = 0.003), median high-sensitivity C-reactive protein (26.4 mg/L vs. 18.9 mg/L, p = 0.045), median WHR (31.8% vs. 27.8%, p = 0.027), median NHR (20.8% vs. 18.3%, p = 0.034), and median MHR (2.2% vs. 1.5%, p < 0.001) levels were higher in the AR group compared to the group without AR. GRACE scores were also higher in the AR group (Table 1).

At 2 weeks post-MI, median infarct size was larger in the AR group compared to the group without AR (20% vs. 15% of LV, p < 0.001), with no differences for other baseline CMR imaging parameters. At 6 months post-MI, mean LVEF was lower in the AR group compared to the group without AR (45.6 ± 10.2% vs. 51.7 ± 9.2%, p < 0.001), while the median LVEDV (175 mL vs. 125 mL, p < 0.001), median LVESV (120 mL vs. 72 mL, p = 0.003), and median infarct size (18% vs. 13% of LV, p < 0.001) were higher in AR group (Table 2).

A positive correlation was found between MHR and infarct size in groups with and without AR (Fig. 1). MHR (OR: 3.21, p = 0.002) and infarct size (OR: 1.09, p = 0.001) were determined as independent predictors of AR. Accordingly, a 1% increase in MHR increased the risk of AR by 3.21-fold (Table 3). MHR showed superior diagnostic performance compared to other indices in predicting AR and the threshold value of MHR was found to be >1.6% with 92.7% sensitivity and 70.1% specificity (AUC ± SE: 0.84 ± 0.03, 95% CI: 0.78-0.88, PPV: 46.8%, NPV: 96.7%, p < 0.001) (Fig. 2A). Mortality risk was 5.62-fold higher in patients with MHR of >1.6 (HR: 5.62, 95% CI: 2.01-15.70, log-rank p < 0.001) (Fig. 2B).

Figure 1 The relationship between MHR and the size of infarct. 

Figure 2 Diagnostic performance of MHR in predicting AR (A) and mortality risk (B). MHR: monocyte to HDL ratio; NHR: neutrophils to HDL ratio; NLR: neutrophils to lymphocytes ratio; PLR: platelets to lymphocytes ratio; WBCs: white blood cells; WHR, WBC to HDL ratio. 

DISCUSSION

To the best of our knowledge, this is the first study to investigate the role of MHR in cardiac remodeling after MI. Admission MHR values were higher among patients who developed AR. A positive correlation was detected between MHR and infarct size in patients with and without AR. It was also determined that MHR is an independent predictor of AR and has high diagnostic performance in predicting AR.

The recovery process after MI includes a complex array of molecular, cellular, and physiological responses that directly affect the pathological and structural changes in the heart and thus the prognosis. A multistage recovery process initiated by the immune system follows acute MI¹⁶. Inflammation is of critical importance in cardiac healing during this recovery process¹⁷. The increased levels of leukocytes, neutrophils, and monocytes and low level of anti-inflammatory HDL-C are important indicators of inflammation. Furthermore, HDL-C can inhibit the activation and migration of leukocytes¹⁸. Following MI, increased leukocyte migration from the spleen to the heart tissue was associated with an increase in specialized pro-resolving lipid mediator production in the myocardium¹⁹. Neutrophils, the first line of defense against inflammation, gather in the ischemic zone to scavenge dead cell debris following MI. The release of reactive oxygen species, granular components, and pro-inflammatory mediators by neutrophils may contribute to myocardial injury²⁰. It has been suggested that the inhibition of monocytes that are recruited in the infarcted myocardium may improve ventricular function²¹. Monocytes are activated by binding to adhesion molecules expressed during the inflammation process²²,²³. Activated monocytes transform into macrophages, which engulf oxidized LDL-C molecules and turn into foam cells. These foam cells facilitate the release of chemokines, cytokines, and growth factors²⁴. HDL-C reduces the activation and adhesion of monocytes, regulates the release of endothelial adhesion molecules, reverses the effects of oxidized LDL-C, and causes vasodilation via the release of nitric oxide⁸,²⁵. This series of events plays an important role in determining the macroscopic structure and geometry of the scarring and has significant effects on cardiac remodeling¹⁶. Therefore, an index generated by leukocytes and their subtypes and HDL-C may be a more important indicator of cardiac healing after MI.

High values of WHR, NHR, and MHR at admission have been demonstrated to be independent inflammatory markers of thrombus burden, prognosis, and cardiovascular events²⁶-²⁹. The prognostic significance of MHR in terms of mortality is consistent with current findings. However, we could not find any study evaluating the relationships between WHR, NHR, and MHR and AR. Current findings indicate that MHR has better diagnostic performance than WHR and NHR in predicting AR. Suzuki et al.³⁰ suggested that the amount of CD14++CD16+ cells in circulation is higher in patients with atrial fibrillation, and this can be associated with left atrial remodeling. Canpolat et al.³¹ suggested that MHR may be an important marker for left atrial remodeling. Values of admission MHR and baseline infarct size were higher in patients with AR, reflecting higher inflammation in the acute phase in infarct areas, but infarct size showed no characteristic healing differences between the groups with and without AR. Nevertheless, there was a positive correlation between infarct size and MHR in both groups and MHR predicted AR regardless of infarct size. These findings might be related to an extremely increased inflammatory response in patients with AR. This is consistent with higher levels of C-reactive protein in patients with AR. In the event of an extremely increased inflammatory response, besides the above mechanisms, higher monocyte counts might negatively affect cardiac recovery²². HDL-C molecules can also prevent the activation and propagation of monocytes while inhibiting activated monocytes³².

Blood parameters are the most commonly available laboratory data during the early period of hospital admission, and they are present universally for the first hour of admission¹⁴. A biomarker that can be easily evaluated in clinical practice would be of critical importance in the classification of high-risk patients, such as those with AR, which is an important predictor of heart failure and poor prognosis. The threshold value of MHR had high diagnostic performance in detecting patients who developed AR, and it was also determined to be an indicator of high risk in terms of mortality. On the other hand, the threshold value of MHR predicting AR is also consistent with the threshold values of MHR predicting mortality or major adverse cardiac events as shown in a previous meta-analysis³³. Therefore, MHR, which is an index that does not increase the costs of patient care and is easy to evaluate in different hospitals that treat MI patients, may be a useful biomarker in cardiac remodeling and mortality risk stratification after MI.

One of the important limitations of this study is that MHR was calculated only at the time of admission. MHR levels after the acute phase of MI were not considered. Another important limitation is that the cytokines that play a role in both AR and inflammatory response were not analyzed. Finally, subtypes of monocytes were not evaluated. Doing so may provide a better understanding of the role of monocytes in the pathophysiology of cardiac remodeling and reveal the prognostic value of MHR levels more clearly.

In conclusion, high admission MHR is an independent predictor of AR at the 6-month follow-up in STEMI patients who have undergone successful primary percutaneous coronary intervention. MHR offers high diagnostic performance for the classification of AR after MI from a prognostic point of view.