Association of Endothelial Nitric Oxyde Synthase (eNOS) Levels and Modifiable Risk Factors for Acute Myocardial Infarction with ST-Segment Elevation (AMI-STE)

Background : The pathological process underlying myocardial infarction is atherosclerotic thrombosis that causes endothelial dysfunction. In the AMI-STE process, eNOS has functions as the body's defense mechanism to prevent more severe damage to the endothelium. Decreased eNOS levels were found in modifiable AMI risk factors. This study aimed to determine the association of eNOS levels based on modifiable risk factors for AMI-STE patients. Methods: This study was an analytical observational study with a historical cohort design. The samples were patients with AMI-STE diagnosis who had undergone PPCI at M. Djamil Hospital Padang from March to June 2022. The eNOS levels were taken from the blood samples. Modifiable AMI risk factors were taken from patient’s medical record. The T test was carried out to determine statistical analysis. Results: The average age of the 38 subjects was 62.53 ± 8.2 years, and 92.1% among them were male, and 52.6% subjects were diagnosed with anterior AMI-STE. The average eNOS level in subjects was 47.47 ± 23.


Introduction
Coronary heart disease (CHD) is one of main problems among all heart diseases.CHD that occurs acutely is known as Acute Myocardial Infarction (AMI) and is one of the main causes of death.Based on the World Health Organization (WHO) report in 2017, around 17.8 million people died due to cardiovascular disease.2] In Indonesia, based on Basic Health Research (RISKESDAS) in 2018, the prevalence of heart disease was 1.5% of the total Indonesian population, in West Sumatra alone the prevalence of heart disease is higher than the national prevalence figure, namely 1.6%, in 2018 based on Riskesdas. 3Exact data on the incidence, morbidity and mortality rates of myocardial infarction in Indonesia are still very limited.Acute Myocardial Infarction with ST-Segment Elevation (AMI-STE), a form of AMI, is a disease that occurs when there is total blockage of the coronary arteries. 4sed on the Jakarta Acute Coronary Syndrome Registry from October 2014 -July 2015, there were 1024 patients with AMI-STE of which 81% underwent primary percutaneous coronary intervention (PPCI). 5Based on the COMPLETE Trial study conducted on AMI-STE patients who underwent PCI in 2019, it was found that the death rate from cardiovascular disease, recurrent AMI, ischemia requiring revascularization, heart failure and unstable angina pectoris accounted for 34.5% of the total 4041 patients. 6e pathological process underlying myocardial infarction is atherosclerotic thrombosis, which is an interaction between susceptible plaque and thrombosis.In myocardial infarction, the inflammatory response plays an important role in the initiation of atherosclerotic plaque and the development of the plaque into a vulnerable plaque, characterized by thin fibrous vesicles, an extensive lipid core, and a large accumulation of inflammatory cells, especially macrophages that are highly susceptible to rupture and form thrombus. 7 The cause of all this is a problem with the endothelium, known as endothelial dysfunction.
Endothelial dysfunction is a decrease in the ability of the endothelium to carry out the functions of blood vessel homeostasis.This decrease in function causes disturbances in blood vessel tone, as well as a condition known as endothelial activation, namely pro-inflammatory, proliferative and pro-coagulation. 8 Decreased eNOS levels were also found in various CHD risk factors.eNOS expression was found to be decreased in metabolic syndrome 11 .
Normal insulin signaling will increase eENOS enzymatic activity.On the other hand, conditions of insulin resistance will disrupt the P13K-Akt pathway which will cause reduced eNOS activity, reduced NO formation and consequently vasoconstriction 12 .Likewise with other CHD risk factors, such as hypertension and dyslipidemia, eNOS levels have also been found to be reduced in various studies.In dyslipidemia, oxidative and non-oxidative LDL will interfere with immunity and regeneration of cells experiencing inflammation.In addition, oxidative LDL inactivates the eNOS/NO pathway 13 21,22 The results of this study showed that overall risk factors were mostly found with low eNOS levels compared with normal ones.eNOS levels had a statistically significant association with diabetes mellitus (p<0.001) and hypertension (p=0.022) as risk factors for AMI-STE.However, statistical tests showed that there was no statistically significant association between eNOS levels and dyslipidemia (p=0.135) and smoking (p=0.346) as risk factors for CHD.
In the AMI-STE process, there is a decrease in eNOS function, where eNOS functions as the body's defense mechanism to prevent more severe endothelial damage. 11In addition, endothelial dysfunction correlates with a decrease in eNOS levels..This can explain why overall risk factors were found more common in low eNOS levels group compared to normal eNOS group.
eNOS expression was found to be decreased in metabolic syndrome. 14In diabetes mellitus, normal insulin signals will increase eENOS enzymatic activity.On the other hand, conditions of insulin resistance will disrupt the P13K-Akt pathway which will cause reduced eNOS activity, reduced NO formation and consequently cause vasoconstriction in AMI-STE. 15,16tivation of eNOS occurs due to explain some of the accelerated atherosclerosis in diabetes. 22kewise with other CHD risk factors, such as hypertension and dyslipidemia, eNOS levels have also been found to be reduced in various studies. 17Decreased levels of nitric oxide (NO) produced by catalyzed endothelial nitric oxide synthase (eNOS) are associated with higher blood pressure.As is known, eNOS produces the compound nitric oxide (NO) which functions as a vasodilator.A decrease in eNOS levels causes a decrease in NO, so that vasodilation will be Decreased endothelial function is reflected in reduced levels of Nitric Oxyde (NO), where NO itself is produced by NO synthase.Currently, 3 isoforms of NO synthase are known and one of them is the largest contributor to NO formation, namely endothelial Nitric Oxide Synthase (eNOS).In the AMI-STE process, eNOS function decreases, where eNOS has functions as the body's defense mechanism to prevent more severe damage to the endothelium. 9In 2016, Abdel Hamid et al conducted research on AMI-STE patients showing that there were circulating endothelial cells and endothelial cell dysfunction which could predict major cardiovascular events such as death, recurrent myocardial infarction and heart failure in patients with AMI-STE. 10 So that the occurrence Endothelial dysfunction correlates with reduced eNOS levels.
transcription factor Sp1.In bovine aortic endothelial cells, hyperglycemia inhibited eNOS activity by 67%.Inhibition of hyperglycemia-associated eNOS was accompanied by a twofold increase in eNOS modification by Olinked N-acetylglucosamine and a decrease in Olinked serine phosphorylation at residue 1117.Inhibition of eNOS and changes in posttranslational modifications were reversed by inhibition of antisense glutamine:fructose-6phosphate amidotransferase, the rate-limiting enzyme of the hexosamine pathway, or by blocking mitochondrial superoxide overproduction by releasing protein-1 (UCP-1) or manganese superoxide dismutase (MnSOD).Chronic changes in eNOS activity through this mechanism may

Table 1 .
Characteristics of Research Subjects 15I-STE but had sepsis, had previous heart surgery, had a history of previous AMI, had burns, had a history of multiple trauma and had stage III as well as stage IV of chronic kidney disease.The sampling technique for this research was simple random sampling, taking samples from the population randomly without paying attention to the strata in the population and each member of the population has the same opportunity to be sampled and meets the research inclusion criteria and selection to be included in the research until the required subjects are met15.The independent variable in this study was eNOS levels, while the dependent variable was modifiable CHD risk factors.The subjects who met the inclusion criteria were then divided into two groups, namely group I with low eNOS level and group 2 with normal eNOS level.Between both groups, the eNOS levels were then compared according to risk factor variables, such as diabetes mellitus, hypertension, dyslipidemia and smoking The research procedures began from subjects who met the research criteria had their eNOS levels checked.The steps taken in this research were blood samples taken during treatment at Dr. M. Djamil Hospital Padang within infarction symptoms.A 3 ml blood sample was taken from a peripheral vein, placed in an EDTA tube.Each specimen that had been centrifuged was then placed into a 1.5 ml micro cup which had been the research variables studied.All analyzes were carried out with the SPSS for Windows computer program.This research has passed ethical review from the Research Ethics Committee, Medical faculty of Andalas University, with letter numbers 602/UN.16.2/KEP-FK/2023.Cardiovascular risk factors in research subjects were smoking, diabetes mellitus, hypertension and dyslipidemia, respectively.Only 1 patient with family history of CHD as one of unmodifiable risk factors was found in this study.More than half (52.6%) of the study subjects were diagnosed with anterior AMI-STE.Most of the research subjects (65%) were patients with Killip class I.

Average eNOS levels of AMI-STE patients undergoing primary percutaneous coronary intervention
13OS levels in healthy subjects are 48.16pg/mL13.This means that the eNOS levels of AMI-STE patients in this study were lower than the normal eNOS level.

Table 2 .
eNOS levels in AMI-STE patients

Table 3 .
Groups of subjects based on eNOS levels

Table 4 .
Association of eNOS Levels with