INFLUENCE OF SYSTEMIC INFLAMMATORY RESPONSE ON IN HOSPITAL OUTCOME IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION UNDERGOING PRIMARY PERCUTANEOUS CORONARY INTERVENTION

Subjects with type 2 diabetes mellitus (T2DM) constitute 13-25% of patients with acute myocardial infarction with ST-segment elevation (STEMI) hospitalized for myocardial reperfusion therapy. The aim of this study was to evaluate systemic inflammatory respo-nse in patients with T2DM and STEMI undergoing primary angioplasty at our clinic and to estimate prognostic significance of inflammatory markers, C-reactive protein (CRP), for inhospital mortality in type 2 diabetics compared to those without diabetes. The retrospective-prospective clinical study included 574 STEMI patients (122 with, and 452 without T2DM), both male and female, who underwent primary percutaneous coronary intervention (pPCI). Examination of the biochemical parameters demonstrated significantly higher concentrations of CRP [med CRP mg/L (25th-75th) 45.0 (12.0 to 101.0) to 25.8 (from 11.3 to 53.7), p=0.013] and glucose levels (12.4±5.9 vs. 7.8±1.9, p=0.001) in subjects with diabetes. There were no differences between the groups rega-rding the activity of CKMB fraction and LDH. Multivariate analysis showed that CRP is an independent prognostic factor of adverse outcome in the first 30 days after primary PCI in non-diabetic group, followed by patient age and smoking (95%CI) [1.012 (1.004-1.020); p=0,004]. In contrast to diabetic patients, a significant mortality in non-diabetics was observed for the third tertile of (95%CI) [1.014 (1.008-1.020); p=0.001]. This findings were presented on the Caplan-Mayer curve. C-reactive protein turned out to be an independent prognostic factor for hospital mortality for the patients without diabetes mellitus type 2 undergoing primary percuta-neous coronary intervention. Acta Medica Medianae 2017;56(2):5-12


Introduction
Type 2 diabetes mellitus (DMT2) is present in 13-25% of patients with acute myocardial infarction with ST-segment elevation (STEMI), admitted to a hospital and undergoing myocardial reperfusion the-rapy (1). They have a worse clinical outcome after primary angioplasty, as well as after fibrinolytic pharmacological reperfusion therapy, compared to STEMI patients without diabetes (2,3). In these patients, elevated levels of inflammatory markers are found, associated with inflammation and adverse clinical outcome (4).
Patients with T2DM and unstable angina pectoris have an inflammatory response similar to non-diabetic patients with STEMI. Both groups have a lower systemic inflammatory response intensity, compared to the group of diabetics with STEMI (5). Elevated levels of C-reactive protein (CRP), a systemic inflammatory response marker measured shortly after STEMI, are associated with dysregulated glucose, confirmed by OGT test during a three-month follow-up (6). C-reactive protein, as well as interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1), both have a role in the onset of insulin resistance (IR). This is indicated by a strict correlation between CRP and concentration of free fatty acids in plasma of the patients with myocardial infarction (7).
Myocardial infarction is thus associated with inflammatory response activation and insulin resistance (8), which is the main characteristic of T2DM. The results are controversial as to the importance of inflammatory response in diagnosing patients with diabetes mellitus and STEMI, who undergo primary percutaneous intervention (9). In the MONICA& CORA register, www.medfak.ni.ac.rs/amm the CRP level on patient admission is a strong risk marker for poor short-term prognosis after myocardial infarction in both diabetics and nondiabetics. However, unlike the patients with-out T2DM, in diabetic patients the admission CRP value was not an independent factor for long-term prognosis (10).
The aim of our study was to assess systemic inflammatory response in patients with DMT2 and STEMI who underwent primary coronary angioplasty at our clinic, and to evaluate prognostic significance of systemic inflammation response markers for in-hospital mortality in diabetic and non-diabetic patients.

Materials and methods
The retrospective-prospective clinical study included 574 patients (122 with type 2 diabetes mellitus and 452 patients without diabetes) with their first STEMI, both male and female, who were treated with primary percutaneous coronary intervention (pPCI). The procedure was performed according to the recommendations of the European Society of Cardiology, in the catheterization department of the Military Medical Academy in Belgrade.
Diabetes was defined as a history of hyperglycemia treated with insulin, hypoglycemic medicaments, or diet. Glycolysated hemoglobin (HbA1c) was used according to the recommendations of the American Diabetes Association (ADA). Patients with HbA1c≥6.5% (48 mmol/mol) were categorized among the patients with DMT2.
On admission, a standard 12-lead electrocardiogram and blood analysis were performed in order to assess creatin-kinase isoenzyme (CK-MB) activity, lactate dehydrogenase enzyme (LDH) acti-vity, glucose blood levels, and concen tration of C-reactive protein. The assessment of heart failure was conducted during clinical exami nation using the Killip classes, and subjects were classified as Killip class 0/1 and Killip˃1. STEMI patients were immediately sent to the cathete rization room, and underwent a standard pPCI procedure after medicamentous preparation.
In the next stage, the patients were monitored in the coronary care unit of the Clinic for Emergency and Internal Medicine of the Military Medical Academy. The dynamics of the enzyme LDH, CK-MB isoenzyme, glucose and CRP as a marker of inflammation was observed in the labora-tory, using the Siemens Dade Behring Dimension RXL Chemistry Analyzer at the Institute of Bioche mistry of the Military Medical Academy in Belgrade. In cases of a chest pain, we repeated coronary angiography to assess the occlusion of the stent. An echocardiography examination was used for each patient, using the apparatus GE Medical Sys tems, mod. Vivid 7 Pro, before their discharge from the hospital. Ejection fraction of the left ventricle (EFLV) was measured using the modified Simpsons method, and Wall Motion Score Index was calculated (WMSI).

Statistic analysis
The results were statistically analyzed using a software for statistical data analysis, "IBM SPSS Statistics", version 20. Data were presented as mean ± SD value and/or percentage. Statistical significance was evaluated by Student's t-test or Mann-Whitney U test, depending on the distribution of the obtained values. We calculated the correlation coefficient (Pearson or Spearman, depending on the distribution of the obtained parameter values) in order to determine interdependence of the monitored parameters. Time to outcome was dete-rmined by the Kaplan-Meyers method. Data will be presented in tables and graphs. A value was considered as statistically significant at p<0.05.

Resultats
A total 574 patients with their first STEMI, who were treated with primary PCI, were monitored, 122 of which suffered from diabetes mellitus type 2 as well ( Figure 1). Their basic demographic and clinical characteristics are presented in Table 1. The patients with type 2 diabetes were signifi cantly older than those without diabetes (64±12ys. vs. 60±12ys.). Both groups had more male then female patients (male-to-female ratio was approxi mately 2:1). Women with STEMI were more often diabetics (p<0.014).

Discussion
The results related to in-hospital mortality did not show any statistically significant difference between the groups of patients with and without diabetes (3.4% versus 5.2%, p = 0.602). This result was not related to HORIZONS AMI study or any other study (11). In this study, 3265 patients with STEMI, of which 533 (16.3%) were with diabetes, demonstrated that mortality after 30 days was significantly higher in diabetic patients (1.8% vs. 4.5%, p=0.0002). The situation was similar with in-hospital mortality resulting from coronary reasons (3.4% vs. 2.6%, p=1.000), in contrast to the results of other studies (12,13).
However, in the HORIZONS AMI study, there were more patients with prior myocardial infarction, prior PCI or CABG in both groups, compared to the patients in our study. Most likely for this reason, a statistically significant difference in in-hospital deaths was not detected.
On the other hand, modern interventional approach to percutaneous coronary intervention is equally successful in both groups, a group of patients with diabetes, and the other group without diabetes. The reason for higher mortality in diabetes group in these studies is less freque ntly achieved restoration of normal myocardial perfusion, measured by "myocardial blush grade" and STsegment resolution, as well as a higher incidence of distal embolization (1,14,15). Our results concerning ST segment resolution did not show any statistically significant difference (37.7% vs. 22.1%, p=0.152) between the groups. CRP and IL-6 and IL-10 were not correlated with the noreflow phenomenon. There was a correlation to arachidonic acid-induced platelet aggregation (AA-IAT) and thromboxane B2 levels, measured before and after PCI. AA-IAT before a PCI proved to be a prognostic factor for the no-reflow phenomenon in diabetics, the sensi tivity of which was 96.2% and specificity 38.5% (16,17).
Patients with diabetes who underwent PCI were older (64±12 years, 60±12 years, p=0.001), and were less likely to smoke, and the frequency of arterial hypertension and hypercholesterolemia was not statistically different between the groups. GUSTO IIb analysis in this study shows a similar relation between diabetics and non-diabetics treated with primary PCI. Patients with diabetes were older, more often women and less often smokers (18).
After examining data regarding the time between the event and patient admission in our study, we found no statistically significant differe nce in "pain-reperfusion time" between diabetics and non-diabetics (p=0.432). Similar results were also found in a recent study, which compa red the time of reporting 62 diabetics and 204 nondiabetics patients with the first presentation of STEMI. The quality and intensity of pain were evaluated using the McGill questionnaire. It was concluded that there was no significant difference in reporting time between the two groups (χ 2 , p=0.105). It was noted that patients with diabe tes who had had multi-vessel coronary disease (χ 2 , p˂0.01) reported last (19). It is very likely that perma-nent and adequate education of the target group of diabetics could improve the out come in these patients. On the other hand, better primary health care organization and wider network of PCI centers contribute to better prognosis in these patients.
Concerning heart failure at admission in the group of patients with diabetes, a frequent occurr-ence of heart failure was observed, ranked as Killip class>1 (24.6% vs. 15.8%, p=0.032). Since coronary angiography prior to intervention did not show more frequent presence of multivessel disease in the group of diabetics, as should be expected, more frequent heart failure on admission was probably the consequence of preexisting myocardial damage in terms of microcirculation disorders and increased extracellular matrix fibrosis in diabetic patients.
In general, in patients with a degree of heart failure present on admission despite pPCI and achieved TIMI-3 flow, suboptimal myocardial reperfusion was observed in a relatively large number of cases. The Killip class at admission was associated with myocardial perfusion, distal embolization, infarction size, maximum enzyme elevation, ejection fraction at discharge and oneyear mortality (20).
The reason for absent differences in the measured ejection fraction and WMSI between the groups was likely to be a short monitoring period.
TIMI-0/1 flow was more common in nondiabetics, compared to TIMI flow before the intervention, while TIMI-2 flow was more frequently noticed in the group of diabetics. This appeared to be probably due to collateral circulation between the coronary arteries in the group of diabetics, causing the maintenance of retro grade filling of infarction-related artery during an infarction in diabetics, which was not present in non-diabetic patients with more frequent TIMI 0/1 flow.
After a pPCI intervention, an equal degree of TIMI 3 flow was observed in both groups, which was consistent to other studies (21).
Thanks to the progress of technology and P2Y12 receptor inhibitor application, and GP IIb/IIIa inhibitors, and with the use of modern scores for bleeding (CRUSADE, ACUITY), periprocedural complications like major bleeding, bleeding in the brain or reinfarction in our study were not more frequent in the group of diabetics.
CRP concentrations were significantly increased in diabetic patients [medCRP mg/L (25th-75th) 45.0 (12.0 to 101.0) to 25.8 (11.3 to 53.7), p = 0.013]. This finding suggested the presence of an intense systemic inflammation in patients with diabetes mellitus (22), although most of myocardial necrosis assessed using CK-MB was no different. It was interesting that studies of the effect of T2DM on myocardial infarction size measured using the scintigraphy with technetium-99m-sestamibi found no significant differences in infarction size between diabetics and non-diabetics who underwent primary PCI (23).
Inflammation has an important role in acute coronary syndrome and in diabetes mellitus type 2. It was found that patients with diabetes and unstable angina have an inflammatory response similar to non-diabetic patients with STEMI. Never theless, both of these groups have a lower systemic inflammatory response intensity compared to the group of diabetics with STEMI (24). Although the blood glucose level at admission is significantly higher in patients with diabetes mellitus, literature data indicate that the highest risk of in-hospital death is present in non-diabetic patients with elevated glucose at admission (25). However, in our study, the elevated levels of blood glucose did not prove to be an independent predictor of death in any of the examined groups of patients. Increased CRP levels recorded early after STEMI were associated with glucose dysregulation, confirmed using the OGT test in a three-month follow-up (6). C-reactive protein, as well as interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1), have a role in the onset of insulin resistance (IR). This is indicated by a strict correlation between IL-6 and CRP and free fatty acid concentration in the blood of patients with myocardial infarction (7).
In this manner, myocardial infarction is associated with the activation of both inflammatory response and insulin resistance (8).
C-reactive protein turned out to be an independent prognostic factor for mortality only in patients with STEMI without diabetes (95% CI) [1.014 (1.008 to 1.020), p=0.001]. A similar conclu-sion was presented in a study which examined the MONICA/KORA myocardial infarction registry. In that study, CRP at admi-ssion was a powerful risk marker of a poor short-term prognosis after myocardial infarction. However, in contrast to the patients without diabetes, CRP at admission was not an independent factor for longterm prognosis in diabetic patients (9).
These findings suggest the need for further investigation of the importance of inflammatory response in ischemic heart disease and diabetes mellitus type 2 due to its close relatedness with the occurrence, development and complications of atherosclerotic disease.

Conclusion
Our study did not reveal any statistically significant difference in total in-hospital mortality and hospital death due to coronary reasons between the groups of patients with and without type 2 diabetes who underwent pPCI due to STEMI. The intensity of a systemic inflammatory response in patients with diabetes was statistically significantly higher, even though the size of the infarction area was not statistically different between the studied groups. Although higher in the T2DM group, C-reactive protein turned out to be an independent progno stic factor for in-hospital mortality only for patients without type 2 diabetes mellitus who underwent pPCI due to STEMI. Dijabetes melitus tip 2 (DMT2) se sreće kod 13-25% bolesnika sa akutnim infarktom miokarda sa elevacijom ST segmenta (STEMI), koji se hospitalizuju radi terapijske reperfuzije miokarda. Kod ovih bolesnika se nalaze i povećane vrednosti markera inflamacije i udruženost inflamacije sa nepovoljnim kliničkim ishodom. Cilj ovog rada bio je da se proceni sistemski inflamatorni odgovor bolesnika sa DMT2 i infarktom miokarda sa ST elevacijom koji se podvrgavaju primarnoj koronarnoj angioplastici na našoj klinici, kao i da se proceni prognostički značaj markera inflamacije, CRP-a za intrahospitalnu smrtnost dijabetičara u odnosu na grupu bolesnika bez dijabetesa.