Endothelial Function Assessment by Flow-Mediated Dilation Method: Comparison
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Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Grzegorz K. Jakubiak.

Cardiovascular diseases (CVDs) in the course of atherosclerosis are one of the most critical public health problems in the world. Endothelial cells synthesize numerous biologically active substances involved in regulating the functions of the cardiovascular system. Endothelial dysfunction is an essential element in the pathogenesis of atherosclerosis. Thus, the assessment of endothelial function in people without overt CVD allows for a more accurate estimate of the risk of developing CVD and cardiovascular events. The assessment of endothelial function is primarily used in scientific research, and to a lesser extent in clinical practice. Among the tools for assessing endothelial function, wthe researchers can distinguish biochemical and physical methods, while physical methods can be divided into invasive and non-invasive methods. Flow-mediated dilation (FMD) is based on the ultrasound assessment of changes in the diameter of the brachial artery as a result of increased blood flow. FMD is a non-invasive, safe, and repeatable test, but it must be performed by qualified and experienced medical staff. 

  • cardiovascular disease
  • endothelial dysfunction
  • flow-mediated dilation

1. FMD in Patients with Obesity, Metabolic Syndrome, and Its Components

1.1. FMD Results in Patients with Obesity

A statistically significant negative correlation was found between the value of the waist circumference and the value of the FMD test result [49][1]. A lower brachial FMD was observed in patients with extreme obesity. Williams et al. and Gluszewska et al. demonstrated that weight loss after bariatric surgery was positively correlated with improved FMD. Both studies aimed to determine whether obesity can influence endothelial function in patients with abnormal FMD results before surgery; after successful intervention, FMD significantly improved in both studies [50,51][2][3]. According to Gluszewska et al., carotid intima-media thickness (IMT) also significantly decreased six months after bariatric surgery. Dominik-Karlowicz et al. conducted a similar study. They showed that, after bariatric surgery, patients arterial performance factors, such as FMD and pulse wave velocity (PWV), improved. However, a negative correlation was observed between FMD and body mass index (BMI) [52][4], which is also reflected in the literature [53][5].
Researchers indicate a multifactorial determination of endothelial impairment. First, visceral adipose tissue has a high bioactive potential [51][3]. Leptin, one of the most essential secretions by adipose tissue, appears to stimulate endothelial inflammatory reactions, making it a proatherogenic substance [54][6]. Interestingly, the dysfunction of perivascular adipose tissue may play a special role in the pathogenesis of CVD [55][7]. Oxidative stress and the increased production of inflammatory cytokines reduce NO secretion, contributing to reduced vasodilation [56][8].
Ne et al. in their meta-analysis, demonstrated that FMD is significantly lower and IMT substantially higher in obese patients. Gender and age did not significantly affect the relationship between obesity and FMD and IMT values. However, there was a significant heterogeneity based on the I2 test [56][8].
Wycherley et al. examined the effect of a low-carbohydrate diet in obese patients with type 2 diabetes mellitus (DM). The switch to a very low carbohydrate diet did not have a significant impact on FMD, despite the reduction in weight and the decrease in HbA1c levels [57][9].

1.2. FMD Results in Patients with Metabolic Syndrome

Metabolic syndrome (MS) is a constellation of abnormalities in energy balance [58][10]. One of the parameters is centrally distributed obesity, which significantly contributes to insulin resistance [59][11] and is directly associated with a higher risk of CVD death [60][12]. It is worth noting that obesity is associated with increased oxidative stress [61][13], and “obesity and insulin resistance” is the MS component that contributes the most to this relationship [62][14]. Oxidative stress plays a vital role in the development of endothelial dysfunction and pathogenesis of atherosclerosis [63,64,65][15][16][17].
Central obesity is a factor that correlates significantly with reduced FMD. Furthermore, reduced FMD in patients with MS increased the risk of cardiovascular events [49][1]. Ryliškytė et al. examined the arterial function and the role of the endothelium in patients with MS using FMD, IMT, aortic augmentation index (Alx), cardio-ankle vascular index (CAVI), and PWV tests. The researchers found that reducing FMD by one standard deviation increases the risk of a cardiovascular incident by 17%. In addition, depending on the IMT score, FMD testing can be used at low cardiovascular risk or for PWV measurements at higher risk. Moreover, patients without a history of CVD had significantly better FMD, IMT, PWV, and mean blood pressure [66][18].
FMD can also be useful in children. Research conducted in 2013, which included 38 obese children and 34 controls, showed that FMD and IMT are valuable methods when identifying patients with increased cardiovascular risk [67][19].

1.3. FMD Results in Patients with Diabetes Mellitus

Lockhart et al. studied FMD in type 1 DM under diastolic shear stress. Their results showed that FMD is significantly impaired in patients with type 1 DM compared to controls. Similarly, endothelium-independent dilatation was considerably damaged in response to glyceryl trinitrate (GTN). Pulse waveform was also different in the study and control group [68][20]. Hamilton et al. also concluded that type 1 DM promotes endothelial dysfunction based on abnormal FMD results, despite the imprecision of the test technique [69][21]. Shivalkar et al. investigated the impact of type 1 DM on cardiovascular risk using FMD and IMT assessment. The results showed a decrease in FMD and an increase in IMT in patients. Regarding the patient’s condition and laboratory tests, FMD was found to be one of the best predictors of cardiac dysfunction in patients with type 1 DM [70][22]. Children with type 1 DM had significantly increased IMT and decreased FMD. Additionally, elevations in markers such as leptin, tumor necrosis factor α (TNF-α), interleukin 4 (IL-4), and high-sensitivity C-reactive protein (hs-CRP) were significantly different between patients with and without diagnosed type 1 DM [71][23].
A significant predictor of future cardiovascular events is coronary artery calcification (CAC), measured by computed tomography. In the study by Ono et al., patients with confirmed CAC and comorbid DM had significantly elevated IMT and reduced FMD. Researchers point to the benefits of combining FMD and IMT to assess cardiovascular risk in patients with DM [72][24]. Barchetta et al. conducted a study to investigate whether elevated inhibitors of dipeptidyl peptidase 4 (DDP-4) activity are correlated with FMD. In a group of 62 patients with type 2 DM, plasma DDP-4 activity was higher than in a control group with the same number of healthy patients. Additionally, DDP-4 values were correlated with higher BMI, waist circumference, the blood level of transaminases, and nonalcoholic fatty liver disease (NAFLD). Finally, FMD values were markedly reduced and associated with elevated plasma DDP-4 activity. However, IMT values were negatively correlated with DDP-4 [73][25]. The contribution of exercise to improvements in endothelial function in patients with type 2 DM was studied by Ghardashi Afousi et al. They showed that low-volume high-intensity interval training (LV-HIIT) for twelve weeks has a significantly positive effect on FMD and caused it to increase [74][26]. The decrease in FMD was not only correlated with the diagnosed DM, but also with elevated fasting glucose levels. In those cases, patients additionally suffered from chronic kidney disease (CKD) [75][27] or MS [49][1]. A decrease in nitroglycerine-mediated flow dilation (NMD) and an increase in IMT were observed in patients with diabetic angiopathy [76][28].

1.4. FMD Results in Patients with Hypertension

Chronic hypertension damages the vessels by inducing inflammation and then the development of atherosclerosis [77][29]. Impaired FMD is highly correlated with at least moderate hypertension. This appears to be related to a reduced ability to produce endothelial nitric oxide [78][30]. IMT, brachial-ankle PWV, and FMD (although less significantly), mainly when performed together, were shown to be a valuable tool to predict the risk of future cardiovascular events risk in elderly patients. Moreover, male gender and hypertension were the most common risk factors for vascular complications [79][31].
The detection of subclinical atherosclerosis is essential to improve patient prognosis. Children of hypertensive parents belong to a particular risk group. A related study was conducted by Evrengul et al. They measured FMD in non-hypertensive offspring of hypertensive parents. They found that offspring of hypertensive parents had lower FMD results than offspring of non-hypertensive parents. The aortic stiffness test noted the same relationship [80][32]. Cetin et al. found an inverse correlation between FMD and left atrial minimum and maximum volumes in hypertensive patients [81][33].

1.5. FMD Results in Patients with Dyslipidemia

Rinkūnienė et al. found a significant relationship between MS, hypertriglyceridemia, and deterioration of arterial performance parameters such as lower IMT and AIx adjusted for a heartrate of 75 beats per minute, as well as higher PWV and mean arterial pressure (MAP). No significant difference was found in FMD value (p = 0.283) [82][34].
The chronic inflammatory process and endothelial dysfunction are the most critical mechanisms in the pathogenesis of atherosclerosis. Statins, the most crucial group of lipid-lowering drugs, also have anti-inflammatory properties. Therapy with a monoclonal antibody targeting interleukin-1β shows promising results and contributes to a reduction in cardiovascular incidents compared to the placebo group [83][35]. Patients with dyslipidemia had lower FMD and higher carotid IMT than the healthy reference group [84][36]. Moran et al. found a significantly higher FMD value in patients with dyslipidemia over the course of resistance to thyroid hormone β than in controls, but no significant difference was found in the IMT value. This may be associated with endothelial hyperreactivity caused by an increase in thyroid hormone levels [85][37].

2. FMD in Patients with Cardiovascular Disease

FMD was shown to play an essential role in assessing cardiovascular event risk. According to a meta-analysis by Inaba et al., the pooled multivariate relative risks of cardiovascular events per 1% and per one standard deviation increase in FMD were 0.872 (95% CI 0.832–0.914) and 0.593 (95% CI 0.490–0.718), respectively [86][38].

2.1. Coronary Artery Disease

Gupta et al. found a substantial decrease in FMD in patients after myocardial infarction compared to controls. Other parameters of vascular function, such as IMT and ankle-brachial index (ABI), were also significantly altered in this population [87][39]. In another study, the parameters of vascular function were assessed in patients with CHD undergoing coronary angiography. A significant decrease in FMD was observed in patients with CHD, and the downward trend continued with the increasing number of diseased coronary vessels and SYNTAX score. Moreover, as the number of diseased vessels increased, the IMT value increased. In addition, the researchers observed the presence of factors that predispose one to CHD, such as age above 69 years, male sex, arterial hypertension, DM, dyslipidemia, low FMD, and high IMT [88][40].

2.2. Peripheral Arterial Disease

In a study in which patients with PAD treated with PTA participated, Kaczmarczyk et al. compared data before the procedure, as well as one, six, and twelve months after PTA. FMD results slightly improved one month after the procedure, but after six months, they decreased to the pre-treatment values. IMT decreased after the PTA procedure compared to before the procedure. ABI first slightly increased, then maintained worse values until the end of the study. Toe-brachial index (TBI) increased after endovascular treatment and remained at one level. Despite the lack of spectacular results in terms of indicators of vascular function, researchers point to the benefits of the PTA procedure due to the clinical improvement in patients, as assessed by pain-free walking distance and maximal walking distance [89][41].

2.3. Chronic Kidney Disease

CVD is the leading cause of death in patients with CKD [90][42]. Changes in biochemical parameters such as ICAM-1 and asymmetric dimethylarginine (ADMA) are frequently observed in patients with CKD and may indicate endothelial damage [91][43]. Patients with CKD have reduced FMD. There is a significant correlation between elevated CRP values and decreased FMD in CKD patients [92][44].
The role of dyslipidemia in endothelial damage is not clear in patients with CKD. Bai et al. showed that in patients with CKD and MS, FMD is significantly lower compared to patients without CKD and without MS. According to a Pearson correlation analysis, FMD was significantly negatively correlated with waist circumference in women (r = −0.223, p = 0.03) and fasting blood glucose (r = −0.186, p = 0.001), while no significant correlation was found between FMD and lipid blood parameters [75][27]. Dogra et al. confirmed that FMD is significantly decreased in patients with CKD when compared to healthy controls. Moreover, dyslipidemia was not associated with vascular dysfunction in CKD patients. Insulin resistance and systolic blood pressure were negatively correlated with FMD in patients with CKD [93][45].
Verbeke et al. found that FMD is significantly decreased in patients with end-stage renal disease (ESRD) without diagnosed CVD compared to controls and is also significantly decreased in patients with coexisting ESRD and CVD [94][46]. In other studies, attenuated FMD was strongly correlated with proteinuria [75,95][27][47].
Impaired FMD was positively correlated with worsening renal glomerular filtration rate but was not associated with increased mortality. Deterioration of the abdominal aortic calcification score, plasma cardiac markers (troponin and natriuretic peptides), and echocardiographic parameter E/e’ contribute to increased mortality in patients with CKD [96][48]. Miyagi et al. confirmed a significant correlation between FMD and estimated glomerular filtration rate (r = 0.31, p = 0.0002), and a significant negative correlation was found between FMD and small artery intimal thickening (r = 0.54, p = 0.0001) [97][49].
After kidney transplantation, improvements in FMD were evident (from 9.1 to 15.7%, p < 0.001) [98][50].

3. FMD Results and Biochemical Changes

Rueda-Clausen et al. show that patients with dyslipidemia and a clinical history of CHD have higher CRP, IL-6, and sVCAM-1 blood levels compared to patients with dyslipidemia and no history of CHD. Elevation of the mentioned markers was associated with higher carotid IMT, but no significant differences were found in FMD [84][36].
Interesting observations were made by Bartoli et al. and Abdou et al. when studying the vascular effects of systemic sclerosis (SSc). According to Bartoli et al., these were significantly reduced in patients with SSc compared to controls (3.41 ± 4.56% vs. 7.66 ± 4.24%; p < 0.037), although no correlation was found between FMD and autoantibody patterns, as well as variables such as disease duration, SSc subset, capillaroscopic pattern, pulmonary involvement, and the presence of digital ulcers [99][51]. Abdou et al. also found that FMD is significantly decreased in patients with SSc. However, FMD is positively correlated with steroid dose (r = 0.385, p = 0.048). Contrary to IMT, FMD did not significantly correlate with CRP concentration [100][52]. However, according to Pacholczak-Madej et al., the decrease in FMD in SSc patients can be partially explained by the increased level of CRP in a simple regression model (β = −0.38, 95% CI −0.55 to −0.22) [101][53].
An important determinant of vascular impairment is oxidative stress. Majer et al. focused on verifying whether vessel function parameters (FMD, ABI, IMT) can correlate with antioxidant vitamin levels (A, D, E) [102][54]. Patients with FMD levels greater than 8.8% were found to have significantly higher plasma concentrations of ascorbic acid, retinol and α-tocopherol than those with FMD below this threshold. Furthermore, vitamin A and E levels were positively correlated with parameters of arterial wall function (FMD) and hemodynamics in lower extremity arteries (ABI), but not with pulse pressure and IMT [102][54]. In a meta-analysis performed by Joris and Mensink, it was confirmed that vitamin E supplementation significantly improves fasting FMD by 2.42% (95% CI 0.46% to 4.37%; p = 0.015) [103][55].
Supplementation with vitamin D in patients with arterial hypertension and type 2 DM was associated with a significant increase in FMD test results and a significant decrease in levels of ox-LDL and ICAM-1 after twelve weeks [104][56]. Vitamin D is associated with calcium metabolism, but receptors for cholecalciferol have also been identified on the surface of endothelial cells [105][57]. This could explain the direct effect of vitamin D on nitric oxide synthesis, which is the primary substance that dilates vessels (including the vasodilation observed in FMD) [106][58]. However, in the above-mentioned meta-analysis performed by Joris and Mensink, no effect of vitamin D supplementation on FMD value was found (0.15%; 95% CI −0.21% to 0.51%; p = 0.41) [103][55], so the effect of vitamin D on endothelial function remains unclear.

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