1. Introduction

Ischemic stroke is the third most common cause of death in the world and also ranks among the most prevalent causes of permanent disability [1]. Acute ischemic stroke (AIS) is defined as an infarction due to arterial occlusion [2]. It is one of the most common neurological emergencies especially in elderly patients with high morbidity and mortality [2, 3]. Large artery atherosclerosis and cardioembolic causes occupy a serious area in the etiology of AIS. Atrial fibrillation (AF) is one of the leading diseases which cause cardioembolic events [3].

Regardless of the etiology of AIS, there is increasing evidence that the inflammatory process plays an important role in the development and prognosis of the disease [4]. The fastest reaction to the vascular occlusive event begins with the response to ischemic damage in the tissue where the occlusion is located. Within this context, functions of monocytes/macrophages and T-lymphocytes are determinant factors in the pathogenesis and outcomes of stroke. They have roles that increase the production of inflammatory cytokines, infiltration and lipids and determine the clinic in patients with AIS, furthering the brain damage caused by ischemia [5].

Microglial cells, which exhibit the fastest response to ischemia, are responsible for this damage in the brain tissue. These cells are resident macrophages of the brain and play a major role in the brisk response [6]. In particular, post-ischemic microglial proliferation peaks 48–72 hours after focal cerebral ischemia and may last for several weeks after the onset of ischemic injury [7]. In addition, reactive microglia cells are morphologically and functionally similar to blood-derived monocytes/macrophages.

Studies have pointed out the activation of microglial cells as the most important factor in proinflammatory damage after ischemia in brain tissue. The effect of macrophages, whose blood counts increase markedly in third-to-seventh days of ischemia on damage is an ongoing debate [8].

Contrary to the fact that the inflammatory response following ischemia both strengthens the atherosclerotic plaque structure and increases the brain damage due to inflammation; high-density lipoprotein cholesterol (HDL-C) exerts anti-inflammatory, antioxidant and antithrombotic effects by reversing cholesterol transport and preventing endothelial dysfunction [9].

Therefore, researchers pointed out that monocyte-to-high-density lipoprotein cholesterol ratio (MHCR) can be a new prognostic biomarker in cardiovascular diseases, ischemic stroke and acute intracerebral hemorrhage (ICH) [10, 11, 12].

AF is the most common cardiac rhythm disorder whose prevalence increases with age. Its prevalence in developed countries is 2% to 4% whilst a 2.3-fold rise is expected, owing to extended life expectancy in the general population and intensifying search for undiagnosed AF [13]. Classifications of AF exist, but are traditionally divided into five classes based on clinical duration and spontaneous termination. This classification includes de novo diagnosis, paroxysmal, persistent, long-standing persistent, and permanent. In patients experiencing both paroxysmal and persistent episodes of AF, it is recommended to use the one which had been recorded more frequently for classification.

In general, AF increases the risk of stroke fivefold when the nonhomogeneous effect of additional risk factors is included [13]. The type of AF also poses a risk at different rates for thromboembolism that will develop in the patient. For example, non-paroxysmal (i.e., persistent or permanent) AF poses a higher risk of thromboembolism than paroxysmal episodes [14]. Although the guidelines still recommend CHA2DS2-VASc scoring for calculating stroke probability and initiating treatment in patients with AF, there are no commonly used and recommended biomarkers to highlight the exact risk for stroke in a given patient. Cardiac troponin T and I, Natriuretic peptides, Cystatin C, Proteinuria, Creatinine Clearance (CrCl)/Estimated Glomerular Filtration Rate (eGFR), C-reactive protein (CRP), interleukin 6 (IL-6), Growth Differentiation Factor-15 (GDF-15), von Willebrand factor (vWF), D-dimer were also advocated in the evaluation of stroke risk in patients with AF in recent years although none of these biomarker-based classifications have been found to possess high predictivity for stroke risk and decision making on treatment [13].

Generally speaking, it is difficult to predict outcomes of diseases in medicine. The process of prediction of functional outcomes after stroke is more challenging given the complex interplay between stroke-related factors (e.g., the degree of severity and subtype of stroke) and associated comorbidities. There are several different risk scores currently in use (i.e., the iScore, the Astral etc.). However, the stroke subtype caused by AF is important in all ischemic stroke patients, because AF alone can lead to mortality in these patients. There are studies on iScore evaluating similar predictive strength in terms of early mortality in this group, but MHCR have been rarely examined. Therefore, the aim of this study is to investigate the usefulness of MHCR, whose components are important biomarkers for atherosclerosis, in predicting the stroke risk of AF patients.

2. Materials and methods

3. Results

Among 92 participants 41.3% (n = 38) were women and mean age was 71.4 $\pm$ 12.07 (range: 36–92). More than three-fourths were older than 65 years old (76.1%, n = 70).

The time to admission into the ED varies between 1 and 3 hours, with an average of 1.70 $\pm$ 0.59 hours. The duration of complaints of the participants ranged from 1 to 240 hours, (mean: 37.63 $\pm$ 56.28 hours). The triage codes were red in 66.3% of the patients (n = 61) and yellow in 33.7% (n = 31). Nearly half of the participants (47.8%, n = 44) were brought to the ED by ambulance, while the others presented with their families or friends. One-fourth of the sample (25.0%, n = 23) have no chronic disease, while the majority (75.0%, n = 69) had at least one comorbid conditions. All of the participants (n = 92) needed radiological examination and consultation. 6.5% (n = 6) were hospitalized in the wards and 93.5% (n = 86) were admitted in the ICU. One patient (1.1%) died during hospitalization and four (4.3%) died within 30 days (Table 1). Systolic blood pressure (BP) ranged from 102 to 235 mmHg with an average of 155.13 $\pm$ 27.98 mmHg, while diastolic blood pressure (BP) ranged from 47 and 124 mmHg with an average of 79.28 $\pm$ 13.88 mmHg.

The relationship of MHCR and systolic BP, diastolic BP, pulse rate, respiratory rate, temperature and O${}_2$ saturation were not found statistically significant (p $>$ 0.05, Table 2).

Four patients who died in 30 days after presentation had significantly higher pulse rates and lower O${}_2$ saturation levels than those who survived(p = 0.005 and p = 0.019, respectively) (Table 3). On the contrary, measurements of systolic BP, diastolic BP, respiratory rate, and temperature were not found to differ significantly with respect to 30-day mortality (p $>$ 0.05). Since patients who died of infectious causes in the hospital were excluded from the study, four patients died in the study period were thought to have died due to cardioembolic causes. Although these deaths have not been confirmed by autopsy studies, there are confirmative radiological evidence.

MHCR did not differ significantly between patients older than 65 years and younger ones (p $>$ 0.05). Likewise, MHCR was not found significantly different between sexes (p = 0.861), and between those with and without chronic diseases (p = 0.510). Cut-off point for the best predictive value of MHCR for 30-day mortality was found to be 0.021. This cut-off has shown a sensitivity of 75%, and specificity of 63.6% (Area under curve: 0.683, 95% CI 0.269–0.992) (Fig. 1).

Fig. 1.Graphic depicting receiver operating characteristic (ROC)analysis of mortality with respect to monocyte HDL-cholesterol ratio (MHCR).

4. Discussion

It is evident that the incidence of ischemic stroke increases globally every year, considering the analyzes published in recent decades [15]. Soaring incidence is explained with the “Dreaded-D’s”, that is, increases in chronic disability, dementia and death, which escalate the pressure of economic, psychological and health problems on the society [16].

Age is among the essential factors affecting the prevalence of AIS. The incidence of the disease increases rapidly with age and doubles every ten years after the age of 55 [17]. The incidence of stroke among adults aged 35 to 44 years is 30 to 120 per 100,000 per year, while it soars up to 670 to 970 in those aged between 65 and 74 years [18]. As age progresses, a parabolic increase in AIS rather than a linear one emerges. Epidemiological stroke studies in Turkey demonstrated that the age range is 35–95 years and the mean age is 64 $\pm$ 14.8 years [19].

The age range of the participants in the present study is 36 to 92, with an average of 71.4 $\pm$ 12.07 years. The higher mean age of patients with stroke in the same city population in the present study can be explained by the recruitment of patients with stroke associated with AF, which represents a more complex profile. The prevalence of AF increases with age, reaching rates of almost 6% to 8% in 75-year-old patients [20, 21]. The age range of the present study corresponds to the elderly population who had a steadily increasing incidence of AF worldwide.

Another factor which has an impact on the outcomes in stroke patients is “early diagnosis-early treatment”. A major cause of long prehospital times is delay in seeking medical attention by the patient or by lay bystanders who have witnessed a stroke [22].

In this study, patients presented to the ED within one to three hours following the onset of their symptoms and this time period falls within the window in which traditional neuroprotective treatment strategies can be pursued [23].

While almost half of the participants of the study presented to the ED as outpatients, half of them were admitted through the emergency health services or ambulances (112-911).

Most of the patients in the study have undergone radiological examination, have been consulted in the early period, and admitted to ICU for treatment and follow-up. The stroke teams were available for the patients with suspected stroke and the guidelines and procedures to be performed in the suspected patients were predetermined. Studies in the literature highlighted that most of the patients who presented to the ED within 3 hours after the onset of stroke symptoms received tissue plasminogen activator (tPA) unacceptably late, which was attributed to the procedures in the hospital [24]. Although some training activities focusing on the early prehospital diagnosis of stroke have been launched in Turkey, most supportive and specific treatment of these patients are administered in the EDs. An interesting point raised in the findings of the study is a majority of the patients (93.5%) was admitted to ICU which is in line with the main rationale of the study encompassing patients with stroke due to AF. Stroke associated with AF carries a substantially higher rates of mortality and morbidity, longer stay in hospital and lower rates of discharge from the hospital when compared to those unaccompanied by AF [25].

The coexistence of AF and stroke in a given patient results in a worse outcome and higher rate of mortality, which gave rise to a research area related to the follow-up of clinical course of these patients in the prehospital field, hospital, stroke units, and ICUs. One of the outstanding research areas involves the value of MHCR in prediction of the patients’ outcomes. The similar phenomena have been studied in many studies related to the predictive role of MHCR. Use of this ratio has proved to be successful in predicting mortality and morbidity of stroke patients [26]. However, there are scarce data focusing on value of MHCR in prediction of outcome of stroke patients associated with AF.

Cardioembolic stroke is a serious condition that accounts for 14–30% of ischemic strokes. Cardioembolic stroke patients are prone to stroke recurrence in the early period, although recurrences can be prevented with appropriate treatment and close follow-up during the acute phase [27].

Since patients who died of infectious causes in the hospital were excluded from analysis, all 4 patients included in the study were thought to be due to cardioembolic causes. Cardioembolic stroke and early recurrent embolization are among the most important determinants of in-hospital mortality.

There is no clearly determined value as a cut-off point for mortality estimates of MHCR. In studies investigating the success of MHCR in estimating mortality, different cut-off values such as 0.28 and 0.51 were identified [26, 28]. In the present study, this ratio was determined as 0.02 with similar sensitivity and specificity values. Researchers investigated this rate in stroke patients in similar geographic populations regardless of the cause of stroke [11]. Analysis of the data unveiled that stroke patients with AF are distinguished from strokes with other etiologies with respect to expectations of mortality and morbidity. This study has shown that the MHCR value, which is frequently studied in the literature, may fail to predict mortality, especially in patients who have had a stroke due to AF.

The study focused on mortality over the 30-day mortality of MHCR in ischemic stroke patients, and although this value failed as a predictive tool in this sample, further studies are needed on the potential association of this ratio with silent microvascular abnormalities and cognitive impairment. Because silent lacunar infarctions have been associated with cognitive impairment in the early stage of cerebral microvascular disease [16, 18].

The present study has some important limitations. Single-center design with a limited sample size may prevent extrapolation of the results to the whole population. Likewise, exclusion of patients with hemorrhagic stroke and those who had no AF on the ECG on presentation prevent us from generalization of the findings.

5. Conclusion

MHCR does not appear to be effective in predicting 30-day mortality in patients with AIS due to AF who presented to the hospital ED. More comprehensive, population-based, multicenter and prospective studies on this subject will be needed to draw sound conclusions.

Author contributions

OA and OK designed the research study. SY and OA performed the research. OA, SY and OK analyzed the data. OA and SY wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The Ethics Committee of the Health Sciences University, Istanbul Training and Research Hospital approved this study (Approval date: 2018 – Approval number: 1398). The need for informed consent has been waived owing to its retrospective nature.

Acknowledgment

Thanks to all the peer reviewers for their opinions and suggestions.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest. Ozgur Karcioglu is serving as one of the Editorial Board members of this journal. We declare that Ozgur Karcioglu had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to WMK.