In this prospective cohort study, brachial artery FMD was performed in a total of 69 ACS hospitalized patients for analysis. The mean age of the patients was 56 ± 9.4 years and most of them were male (75.4%). There were 17 patients (24.6%) with FMD < 5% that was considered ED in this study. Then the patient was followed-up to determine the MACE that occurred during in-hospital, 1 month, and 6 months after hospitalization. Only 1 patient had in-hospital MACE, while during 1 month and 6 months follow-up there were 10 and 17 patients had MACE, respectively. The aim of this study was to determine ED by brachial artery FMD as a predictor of MACE in that time period.
The endothelium is involved in controlling vasomotor tone, blood fluidity, and the local balance of pro- and anti-inflammatory mediators, as well as procoagulant and anticoagulant activities.23 NO is the most significant endothelium-derived factor, acting as a vasodilator, inhibiting platelet aggregation and leukocyte adhesion, reducing vascular smooth muscle cell migration and proliferation, and regulating oxidative stress and inflammation.24,25 ED is a condition of relaxation and constriction of blood vessels imbalance resulting from reduced production and/or bioavailability of NO that is important in determining thrombogenesis and plaque vulnerability to rupture in CVD.6,26 Several studies have shown that the process of ED in response to genetic and environmental risk factors, has occurred long before clinical cardiovascular disease emerged.27,28 In addition, ED has an independent prognostic value of acute cardiovascular events in CAD. As many as 70% of subjects with AMI and/or sudden coronary death were due to plaque rupture in patients with no previous history of high risk factors for atherosclerotic disease. The factors that influence plaque rupture are not necessarily the same as those that lead to atherosclerotic formation.29
The traditional risk factors that were collected and analysed as confounding factors for the occurrence of MACE in this study included age, hypertension, DM, dyslipidemia, and smoking history. The percentage of patients who had hypertension was 53.6%, DM 30.4%, dyslipidemia 76.8%, and smoking history 53.6%. Several prospective studies suggest that all of these comorbidities are at risk for MACE.30 However, in this study, only DM was found to have a significant correlation to 6 months follow-up MACE (RR 2.57; 95% CI = 1.15–5.73; p = 0.043). After multivariate analysis, DM was a predictor of 6 months follow-up MACE, but not the strongest predictor (Exp B 6.33; 95%CI = 1.37–29.22; p = 0.014). This is consistent with several studies.20,31,32
Endothelial function assessment can identify “susceptible” patients who are at high risk for recurrence of cardiovascular complications following an ACS.33 FMD has been shown to have prognostic value in later cardiovascular disease (CVD), which may be better than traditional risk factors.10,34,35 This prognostic utility is consistent across various population subgroups, although heterogeneity between studies and between subgroups was found.10 A meta-analysis that summarized 14 prospective studies reported that per 1% higher FMD value, the risk of experiencing a cardiovascular event was found to be 13% lower.36 Sawada et al. reported that low FMD value indicates overall coronary artery vulnerability and that patients are at increased risk of MACE compared with patients with high FMD value.13
Brachial artery FMD examination in this study was carried out with the recommended subject preparation and protocol.11,17 It used a stereotactic clamp fitted to the ultrasound probe, a modified patient hand fixator, and commercial software for arterial edge detection, thereby increasing objectivity and accuracy in this study. Because medication therapy for CAD has direct and indirect vascular effects, if possible, subjects should not take all medications for ≥4 half-lives of the drug before FMD examination or at least 6 hours fasting to minimize drug effect. However, if this is not possible, because discontinuation of the drug can pose a risk to the patient's cardiovascular disease, documentation and analysis of confounding medications is needed.11,37 In this study, there was a significant correlation only on statin medication to FMD < 5% (RR 0.31; 95%CI = 0.14–0.65; p = 0.029). In accordance with a study examining 1081 CAD patients, with at least 7 days of statin therapy, an independent effect was found on improving FMD value, independent of the lipid-lowering effect at a later date.38
In the analysis of the correlation between FMD < 5% with in-hospital, first and sixth months follow-up MACE, there was a significant correlation between first and sixth months follow-up MACE with p=0.001 and p < 0.001, respectively. The presence of FMD < 5% increased 1 month follow-up MACE by 7.13 times (95% CI = 2.07–24.58; p = 0.001) and increased 6 months follow-up MACE by 5.60 times (95% CI = 2.44–12.86; p < 0.001). For in-hospital MACE, there was no significant correlation with FMD value. In multivariate analysis with other variables having p < 0.250, FMD < 5% was the strongest predictor compared to multivessel CVD for 1 month follow-up MACE (p = 0.001). At 6 months of follow-up, FMD < 5% was still the strongest predictor compared to DM and beta blocker medication (p = < 0.001). This has confirmed several previous studies and meta-analyses, which have shown that FMD value was reported as predictors of MACE.13,35,36,39,40
After knowing the magnitude of the role of ED with brachial artery FMD on predicting MACE, it should be noted that the management of conditions related to improving FMD value must be carried out aggressively. Modena et al. found that increased FMD value indicated people with a better outcome for cardiovascular event after management of other risk factors, such as blood pressure, in hypertensive postmenopausal women.41 Kitta et al. found that persistent and unfavourable FMD values following CAD risk factor treatment were independent predictors of cardiovascular events.42 Takishima et al. recently revealed that in patients with stable chronic ischemic heart failure, persistently low FMD values after effective treatment for heart failure and atherosclerotic risk factors were independent predictors of cardiac events, even when other risk factors were successfully managed.43 Overall, these findings indicate that patients may gain benefit from endothelial function-improving therapy.35 CAD patients with ED by brachial artery FMD are recommended to be given optimal therapy against atherosclerosis risk factors to prevent MACE.19