Normalization Of Flow-mediated Dilation Research Articles

Normalization of Flow-mediated Dilation to Brachial Artery Material Property: A Feasibility Study.

Endothelial reactivity (ER) is widely measured using flow-mediated dilation (FMD) of brachial artery. Conventional measurement of FMD is influenced by factors such as input shear stress, arterial transmural pressure, diameter and thereby arterial material properties (ε). Thus, for a reliable interpretation of FMD, it has to be normalized with respect to the above confounding factors. Normalization of FMD with shear stress at the time of measurement has been reported to reduce measurement variability. However, its widespread usage among the research community is limited. In this work, we examine the feasibility of normalizing the brachial FMD index (FMD%) to ε : extrema (εp), baseline (εb) and extrema change (∆ε) post-ischemia using its inter-day variability against FMD. In-vivo measurements were performed on 10 participants for 2 consecutive days and simultaneous pressure-diameter cycles were collected to estimate the material properties during reactive hyperemia (RH). The box-whisker plot reveals differences in the mean and deviation of FMD to FMD|εb. A significant value for repeatability (ICC ≥ 0.6) was obtained for normalized FMD (FMD|εb) for specific stiffness index (β), pressure-strain elastic modulus (Ep), and local pulse wave velocity (PWV) as compared to FMD. Hence, normalization of FMD% to arterial ε can potentially improve the measurement reliability of ER assessment.Clinical Relevance- This pilot study demonstrates the feasibility of brachial artery stiffness assessment during FMD and its potential use for normalizing the standard FMD measurement.

Reference Intervals for Brachial Artery Flow-Mediated Dilation and the Relation With Cardiovascular Risk Factors.

[Figure: see text].

DOES FLOW-MEDIATED DILATION NORMALIZATION FOR BASE-SCALED SHEAR RATE IMPROVE ITS VALUE IN CORONARY ARTERY DISEASE DIAGNOSTICS?

The article presents a new normalization of flow-mediated dilation (FMD) in the radial artery, taking into account the parameter BSSR being equal to the ratio of the basal shear rate (BS) measured before the cuff inflation and post occlusive shear rate (SR). The in vivo usefulness of the new normalization algorithm was evaluated in two groups of patients. In group I, comprising 15 healthy volunteers, the normalized FMD/SR was (3.19 ± 1.4)•10-4, while in group II, comprising 13 patients with stable coronary artery disease (CAD), it was (1.02 ± 0.76)•10-4. We calculated almost 50% larger difference between the average values after normalizing FMD/BSSR. Specifically, the FMD/BSSR was equal to 28 ± 9.40 in group I and 6.01 ± 3.74 in group II. The prediction of CAD patients based on FMD/SR values had a sensitivity of 83.3% and a specificity of 84.6%, whereas the prediction of CAD patients based on the FMD/BSSR values revealed 100% sensitivity and specificity. These results confirm the usefulness of the novel normalization algorithm of the FMD in differentiation of normal patients from those with stable CAD.

Characterization of blood flow patterns and endothelial shear stress during flow‐mediated dilation

Endothelial dysfunction is considered the first step in the development of atherosclerosis. Flow-mediated dilation (FMD) has been the most common assessment of endothelial function in research but it has failed in obtaining a widespread use in clinical settings due to a lack of standardization and a large inter-subject variability. Normalization of FMD to endothelial shear stress (ESS) has been proposed to solve its technical limitations. However, studies have not considered the characteristic of the blood flow during FMD under pulsatile conditions in their ESS estimations. A total of 26 young healthy subjects (15 females and 11 males) underwent FMD testing. Microhematocrit measurement was used to determine blood viscosity (μ). ESS was calculated by Womersley's approximation, ESS= μ*2K*Velocity/Diameter, where K is a function of Womersley's parameter (α). Blood flow patterns were determined by critical Reynolds number. Statistical analysis included repeated measures ANOVA to detect ESS differences during FMD until peak dilation. Significance was established at P≤0.05. The mean (SD) FMD% and time to peak dilation were 7·4 (3·1) % and 35 (9·3) seconds, respectively. ESS was significantly reduced during FMD until peak dilation (P<0·001). Turbulent blood flow was the only pattern observed until peak dilation in 96·15% of the sample. Peak FMD dilation in a young healthy population is triggered mostly by high-ESS under turbulent flow conditions. Due to the pulsatile nature of blood flow and the appearance of a turbulent pattern during FMD, ESS should be estimated by Womersley's approximation rather than Poiseuille's law.

Cardiorespiratory fitness modulates the acute flow-mediated dilation response following high-intensity but not moderate-intensity exercise in elderly men.

Impaired endothelial function is observed with aging and in those with low cardiorespiratory fitness (V̇o2peak). Improvements in endothelial function with exercise training are somewhat dependent on the intensity of exercise. While the acute stimulus for this improvement is not completely understood, it may, in part, be due to the flow-mediated dilation (FMD) response to acute exercise. We examined the hypothesis that exercise intensity alters the brachial (systemic) FMD response in elderly men and is modulated by V̇o2peak Forty-seven elderly men were stratified into lower (V̇o2peak = 24.3 ± 2.9 ml·kg-1·min-1; n = 27) and higher fit groups (V̇o2peak = 35.4 ± 5.5 ml·kg-1·min-1; n = 20) after a test of cycling peak power output (PPO). In randomized order, participants undertook moderate-intensity continuous exercise (MICE; 40% PPO) or high-intensity interval cycling exercise (HIIE; 70% PPO) or no-exercise control. Brachial FMD was assessed at rest and 10 and 60 min after exercise. FMD increased after MICE in both groups {increase of 0.86% [95% confidence interval (CI), 0.17-1.56], P = 0.01} and normalized after 60 min. In the lower fit group, FMD was reduced after HIIE [reduction of 0.85% (95% CI, 0.12-1.58), P = 0.02] and remained decreased at 60 min. In the higher fit group, FMD was unchanged immediately after HIIE and increased after 60 min [increase of 1.52% (95% CI, 0.41-2.62), P < 0.01, which was correlated with V̇o2peak, r = 0.41; P < 0.01]. In the no-exercise control, FMD was reduced in both groups after 60 min (P = 0.05). Exercise intensity alters the acute FMD response in elderly men and V̇o2peak modulates the FMD response following HIIE but not MICE. The sustained decrease in FMD in the lower fit group following HIIE may represent a signal for vascular adaptation or endothelial fatigue.NEW & NOTEWORTHY This study is the first to show that moderate-intensity continuous cycling exercise increased flow-mediated dilation (FMD) transiently before normalization of FMD after 1 h, irrespective of cardiorespiratory fitness level in elderly men. Interestingly, we show increased FMD after high-intensity cycling exercise in higher fit men, with a sustained reduction in FMD in lower fit men. The prolonged reduction in FMD after high-intensity cycling exercise may be associated with future vascular adaptation but may also reflect a period of increased cardiovascular risk in lower fit elderly men.

Impaired Vascular Function in Physically Active Premenopausal Women With Functional Hypothalamic Amenorrhea Is Associated With Low Shear Stress and Increased Vascular Tone

Exercise-trained hypoestrogenic premenopausal women with functional hypothalamic amenorrhea (ExFHA) exhibit impaired endothelial function. The vascular effects of an acute bout of exercise, a potent nitric oxide stimulus, in these women are unknown. Three groups were studied: recreationally active ExFHA women (n = 12; 24.2 ± 1.2 years of age; mean ± SEM), and recreationally active (ExOv; n = 14; 23.5 ± 1.2 years of age) and sedentary (SedOv; n = 15; 23.1 ± 0.5 years of age) ovulatory eumenorrheic women. Calf blood flow (CBF) and brachial artery flow-mediated dilation (FMD) were evaluated using plethysmographic and ultrasound techniques, respectively, both before and 1 hour after 45 minutes of moderate-intensity exercise. Endothelium-independent dilation was assessed at baseline using glyceryl trinitrate. Calf vascular resistance (CVR) and brachial peak shear rate, as determined by the area under the curve (SRAUCpk), were also calculated. FMD and glyceryl trinitrate responses were lower (P < .05) in ExFHA (2.8% ± 0.4% and 11.6% ± 0.7%, respectively) than ExOv (8.8% ± 0.7% and 16.7% ± 1.3%) and SedOv (8.0% ± 0.5% and 17.1% ± 1.8%). SRAUCpk was also lower (P < .05) in ExFHA. Normalization of FMD for SRAUCpk (FMD/SRAUCpk) did not alter (P > .05) the findings. CBF was lower (P < .05) and CVR higher (P < .05) in ExFHA. After exercise, FMD and SRAUCpk were augmented (P < .05), but remained lower (P < .05), in ExFHA. FMD/SRAUCpk no longer differed (P > .05) between the groups. CBF in ExFHA was increased (P < .05) and CVR decreased (P < .05) to levels observed in ovulatory women. Acute dynamic exercise improves vascular function in ExFHA women. Although the role of estrogen deficiency per se is unclear, our findings suggest that low shear rate and increased vasoconstrictor tone may play a role in impaired basal vascular function in these women.

Endothelial dysfunction, increased inflammation, and activated coagulation in HIV‐infected patients improve after initiation of highly active antiretroviral therapy

Endothelial dysfunction and inflammation have been demonstrated to be markers of cardiovascular risk. We investigated the effects of HIV infection per se and the antiretroviral treatment prescribed on the levels of risk factors of cardiovascular disease. This was a prospective study of 20 treatment-naïve, nonsmoking, HIV-positive patients examined before and after 3 months of treatment with a protease inhibitor (PI)-containing regimen followed by 3 months of treatment with nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing therapy. Parameters of inflammation, endothelial function and coagulation were examined. The results were compared with those for an age- and gender-matched, nonsmoking, healthy control group. Compared with controls, treatment-naïve HIV-infected patients exhibited endothelial dysfunction [flow-mediated dilation (FMD) 108 vs. 111% for HIV-infected vs. control groups, respectively; P < 0.05] and activation [von Willebrand factor 2.0 vs. 0.9 U/l; soluble intercellular adhesion molecule (sICAM) 313 vs. 211 ng/L, respectively; P < 0.01]. Inflammation [C-reactive protein (CRP) 24 vs. 8.6 nmol/L; fibrinogen 9.4 vs. 8.6 μmol/L, respectively; P < 0.05] and coagulation/fibrinolysis (D-dimers 0.55 vs. 0.23 μg/mL, respectively; P < 0.01) were increased. Initiating therapy resulted in normalization of FMD and a significant decrease in endothelial activation and CRP. Endothelial dysfunction together with increased inflammation and coagulation were more prevalent in untreated HIV-infected patients compared with controls. These cardiovascular risk factors improved with treatment, although not all parameters normalized after 6 months.

Intermittent exercise abolishes the diurnal variation in endothelial-dependent flow-mediated dilation in humans

It is currently unclear to what extent diurnal variation and exercise effect endothelium-dependent nitric oxide (NO)-mediated vasodilation. Therefore, we measured brachial artery flow-mediated dilation (FMD) in 10 males (mean age = 28 yr, SD = 7), before and after a bout of intermittent cycling at 70% peak oxygen uptake on separate days beginning either at 0800 or 1600. Edge-detection and wall-tracking software was used to measure changes in arterial diameter, while shear rate (SR) was assessed using simultaneously derived blood flow velocity and B-mode diameter data. The FMD data were analyzed before and after normalization for SR with repeated-measures models. Before exercise, mean + or - SD FMD was 7 + or - 3% in the morning compared with 11 + or - 6% in the afternoon (P = 0.01). This diurnal variation persisted after data were normalized for SR, which was found to be unaffected by time of day (P = 0.33). Postexercise SR was higher than at baseline (pre-exercise) (P = 0.01) to a similar extent at both times of day. FMD was unaffected by exercise in the morning (P = 0.96) but decreased by 4 + or - 3% following exercise in the afternoon (P = 0.01) so that postexercise measurements did not differ between times of day. These data indicate that endothelium-dependent FMD is lower in the morning, and this finding was not altered by normalization of FMD for diurnal variation in SR. This infers a reduced function of the intrinsic endothelial NO-vasodilator system in the morning. We also report, for the first time, that a bout of intermittent exercise abolishes this diurnal variation in endothelium-dependent FMD.

Normalization Of Flow Mediated Dilation To Time-to-Peak Improves Measurement Sensitivity

Normalization Of Flow Mediated Dilation To Time-to-Peak Improves Measurement Sensitivity

Normalization of flow-mediated dilation to shear stress area under the curve eliminates the impact of variable hyperemic stimulus

BackgroundNormalization of brachial artery flow-mediated dilation (FMD) to individual shear stress area under the curve (peak FMD:SSAUC ratio) has recently been proposed as an approach to control for the large inter-subject variability in reactive hyperemia-induced shear stress; however, the adoption of this approach among researchers has been slow. The present study was designed to further examine the efficacy of FMD normalization to shear stress in reducing measurement variability.MethodsFive different magnitudes of reactive hyperemia-induced shear stress were applied to 20 healthy, physically active young adults (25.3 ± 0. 6 yrs; 10 men, 10 women) by manipulating forearm cuff occlusion duration: 1, 2, 3, 4, and 5 min, in a randomized order. A venous blood draw was performed for determination of baseline whole blood viscosity and hematocrit. The magnitude of occlusion-induced forearm ischemia was quantified by dual-wavelength near-infrared spectrometry (NIRS). Brachial artery diameters and velocities were obtained via high-resolution ultrasound. The SSAUC was individually calculated for the duration of time-to-peak dilation.ResultsOne-way repeated measures ANOVA demonstrated distinct magnitudes of occlusion-induced ischemia (volume and peak), hyperemic shear stress, and peak FMD responses (all p < 0.0001) across forearm occlusion durations. Differences in peak FMD were abolished when normalizing FMD to SSAUC (p = 0.785).ConclusionOur data confirm that normalization of FMD to SSAUC eliminates the influences of variable shear stress and solidifies the utility of FMD:SSAUC ratio as an index of endothelial function.

Reply to Drs. Harris and Padilla

Reply : We welcome the recent letter from Harris and Padilla ([4][1]) and are hopeful that the proposed analysis of covariance (ANCOVA) approach to normalize flow-mediated dilation (FMD) for shear stimulus might provide an advancement of importance in this area. FMD in response to a 5-min forearm

Análisis de las diferencias encontradas en la dilatación mediada por flujo según la terapia seguida en pacientes con enfermedad coronaria

Flow-mediated dilation (FMD) is thought to be related to the development of coronary disease. We were interested in knowing the degree of FMD in a large sample of coronary patients in relation to the therapy they were given in clinical practice. We studied 1,081 coronary patients (age 68 +/- 12 years, 73% male) in which FMD was evaluated in the brachial artery. The patients were classified into 5 treatment groups (416 who receive 2 or more treatments were excluded): group A: 81 controls treated with aspirin, group B: 198 treated with ACE inhibitors, group C: 106 with calcium antagonists, group D: 145 with beta-blockers, and group E: 135 with lipid lowering medication (93% statins). ANOVA was used to analyze the differences between groups. With regard to the number of risk factors present in each group, the patients treated with ACE inhibitors (2.44 +/- 0.79 vs 2.14 +/- 0.89; p < 0.05) and statins (3.45 +/- 0.70 vs 2.14 +/- 0.89; p < 0.05) had more risk factors than GrA and higher levels of LDL-cholesterol (ACE inhibitors 145.0 +/- 33.5 vs 128.5 +/- 32.2 and statins 157.8 +/- 45.3 vs 128.5 +/- 32.2; p < 0.05). GrB had a higher glycemia than controls (123.4 +/- 32.2 vs 114.7 +/- 33.7; p < 0.05). The control group was younger than the therapeutic groups (p < 0.05). Compared with the control group, FMD was significantly higher only in the group treated with ACE inhibitors (3.42 +/- 6.01 vs 0.82 +/- 6.04; p < 0.05). Multivariate logistical regression showed that treatment with ACE inhibitors and statins (p < 0.05) were independent predictors of FMD > 4%. Treatment with ACE inhibitors or statins was predictive of the normalization of FMD in coronary patients in clinical practice.