OCTAVA: An open-source toolbox for quantitative analysis of optical coherence tomography angiography images

Optical coherence tomography angiography (OCTA) performs non-invasive visualization and characterization of microvasculature in research and clinical applications mainly in ophthalmology and dermatology. A wide variety of instruments, imaging protocols, processing methods and metrics have been used to describe the microvasculature, such that comparing different study outcomes is currently not feasible. With the goal of contributing to standardization of OCTA data analysis, we report a user-friendly, open-source toolbox, OCTAVA (OCTA Vascular Analyzer), to automate the pre-processing, segmentation, and quantitative analysis of en face OCTA maximum intensity projection images in a standardized workflow. We present each analysis step, including optimization of filtering and choice of segmentation algorithm, and definition of metrics. We perform quantitative analysis of OCTA images from different commercial and non-commercial instruments and samples and show OCTAVA can accurately and reproducibly determine metrics for characterization of microvasculature. Wide adoption could enable studies and aggregation of data on a scale sufficient to develop reliable microvascular biomarkers for early detection, and to guide treatment, of microvascular disease

Assessing Variability in Vascular Response to Cocoa With Personal Devices:A Series of Double-Blind Randomized Crossover n-of-1 Trials

Controlled clinical intervention studies have demonstrated that cocoa flavanols (CF) can decrease blood pressure and arterial stiffness in healthy humans, although a large variability in the effect size across trials has been reported. Here, we evaluated intra- and inter-individual variability of responses to CF in everyday life using a series of n-of-1 trials in healthy free-living individuals with normal blood pressure carrying personal devices. Eleven healthy young humans participated in a repeated cross-over randomized controlled double-blind n-of-1 trial. On eight consecutive days, each volunteer consumed on alternating days 6 CF capsules (862 mg CF) on four days and 6 matched placebo capsules (P, 0 mg CF/day) on another 4 days in one of two randomized sequences (CF-P-CF-P-CF-P-CF-P or P-CF-P-CF-P-CF-P-CF). On each day the capsules were taken at the same time in the morning with breakfast after baseline measurements. Each subject was provided with an upper arm blood pressure monitor and a finger clip that measures pulse wave velocity (PWV). Measurements of blood pressure, heart rate and PWV were taken at least hourly over 12 hours during the day by the participants. On the first 2 days measurements were performed under supervision to provide training. The overall mixed model analysis showed that CF significantly decreased 12 h systolic blood pressure and PWV by -1.4±0.3 mmHg and - -0.11±0.03 m/s, respectively. Peak effects were observed within the first 3 hours (1.5 h SBP: -4.9±2.2 mmHg, PWV: -0.32±0.17 m/s)and again after 8 h post ingestion. Large inter-individual variation in responses was found (intra-cluster correlation coefficients [ICC]: 0.41, 0.41). When analysing single individuals’ datasets, there was also considerable between-day variation in individual responses that varied greatly between subjects (ICC: 0-0.30, 0-0.22, 0-0.45). Effect sizes inversely correlated with baseline blood pressure values both between-- and within-subjects. The data confirm that cocoa can decrease blood pressure and arterial stiffness in everyday life when elevated within the normal range. The large inter- and intra-individual variation in responses call for more personalized nutritional intervention strategies.</p

Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health

Aims: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper is to assess FMD values in apparently healthy individuals and provide reference values to facilitate wider clinical use.Methods and Results: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body-mass-index, glucose, cholesterol, blood pressure, and brachial artery diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and brachial artery diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller brachial artery diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (c=0.841, p) showed that FMD of >6.5%&nbsp;excluded CAD (95% sensitivity; 60% specificity) and FMD I2=0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2=0.13).Conclusions: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of CV health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.</p

Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared to a MUFA-rich oil: A randomized controlled trial

Background: Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism.Objective: To test the impact of a commonly consumed IE versus a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil (rapeseed oil; RO).Design: A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n=20) aged 45-75 years. Postprandial plasma triacylglycerol (TG) and lipoprotein responses (including stable isotope tracing) to a test meal (50g fat) were evaluated over 8 hours. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM).Results: Plasma TG 8h incremental area under the curves were lower following non-IE versus RO (-1.7 mmol/L.h (95% confidence interval -3.3, -0.0)), but there were no differences between IE and RO nor IE and non-IE. Low density lipoprotein (LDL) particles were smaller following IE and non-IE versus RO (P=0.005). Extra, extra large (XXL)-, extra large (XL)- and large (L)- VLDL particle concentrations were higher following IE and non-IE versus RO at 6-8 h (P <0.05). No differences in the appearance of [13C]palmitic acid in plasma TG was observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of saturated fatty acids (SFA) versus RO.Conclusions: Interesterification did not modify fat digestion, postprandial lipemia or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA rich fats, increased pro-atherogenic large TG-rich lipoprotein remnant and small LDL particles following the SFA rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFA to cardiovascular disease risk

Pilot study of optical coherence tomography angiography-derived microvascular metrics in hands and feet of healthy and diabetic people

Abstract Optical coherence tomography angiography (OCTA) is a non-invasive, high-resolution imaging modality with growing application in dermatology and microvascular assessment. Accepted reference values for OCTA-derived microvascular parameters in skin do not yet exist but need to be established to drive OCTA into the clinic. In this pilot study, we assess a range of OCTA microvascular metrics at rest and after post-occlusive reactive hyperaemia (PORH) in the hands and feet of 52 healthy people and 11 people with well-controlled type 2 diabetes mellitus (T2DM). We calculate each metric, measure test–retest repeatability, and evaluate correlation with demographic risk factors. Our study delivers extremity-specific, age-dependent reference values and coefficients of repeatability of nine microvascular metrics at baseline and at the maximum of PORH. Significant differences are not seen for age-dependent microvascular metrics in hand, but they are present for several metrics in the foot. Significant differences are observed between hand and foot, both at baseline and maximum PORH, for most of the microvascular metrics with generally higher values in the hand. Despite a large variability over a range of individuals, as is expected based on heterogeneous ageing phenotypes of the population, the test–retest repeatability is 3.5% to 18% of the mean value for all metrics, which highlights the opportunities for OCTA-based studies in larger cohorts, for longitudinal monitoring, and for assessing the efficacy of interventions. Additionally, branchpoint density in the hand and foot and changes in vessel diameter in response to PORH stood out as good discriminators between healthy and T2DM groups, which indicates their potential value as biomarkers. This study, building on our previous work, represents a further step towards standardised OCTA in clinical practice and research

Cocoa flavanol consumption improves lower extremity endothelial function in healthy individuals and people with type 2 diabetes

BACKGROUND: diabetes and age are major risk factors for the development of lower extremity peripheral artery disease (PAD). Cocoa flavanol (CF) consumption is associated with lower risk for PAD and improves brachial artery (BA) endothelial function. OBJECTIVES: to assess if femoral artery (FA) endothelial function and dermal microcirculation are impaired in individuals with type 2 diabetes mellitus (T2DM) and evaluate the acute effect of CF consumption on FA endothelial function. METHODS: in a randomised, controlled, double-blind, cross-over study, 22 individuals (n = 11 healthy, n = 11 T2DM) without cardiovascular disease were recruited. Participants received either 1350 mg CF or placebo capsules on 2 separate days in random order. Endothelial function was measured as flow-mediated dilation (FMD) using ultrasound of the common FA and the BA before and 2 hours after interventions. The cutaneous microvasculature was assessed using optical coherence tomography angiography. RESULTS: baseline FA-FMD and BA-FMD were significantly lower in T2DM (FA: 3.2 ± 1.1% [SD], BA: 4.8 ± 0.8%) compared to healthy (FA: 5.5 ± 0.7%, BA: 6.0 ± 0.8%); each p < 0.001. Whereas in healthy individuals FA-FMD did not significantly differ from BA-FMD (p = 0.144), FA-FMD was significantly lower than BA-FMD in T2DM (p = 0.003) indicating pronounced and additional endothelial dysfunction of lower limb arteries (FA-FMD/BA-FMD: 94 ± 14% [healthy] vs. 68 ± 22% [T2DM], p = 0.007). The baseline FA blood flow rate (0.42 ± 0.23 vs. 0.73 ± 0.35 l min-1, p = 0.037) and microvascular dilation in response to occlusion in hands and feet were significantly lower in T2DM subjects than in healthy ones. CF increased both FA- and BA-FMD at 2 hours, compared to placebo, in both healthy and T2DM subgroups (FA-FMD effect: 2.9 ± 1.4%, BA-FMD effect 3.0 ± 3.5%, each pintervention< 0.001). In parallel, baseline FA blood flow and microvascular diameter significantly increased in feet (3.5 ± 3.5 μm, pintervention< 0.001) but not hands. Systolic blood pressure and pulse wave velocity significantly decreased after CF in both subgroups (-7.2 ± 9.6 mmHg, pintervention = 0.004; -1.3 ± 1.3 m s-1, pintervention = 0.002). CONCLUSIONS: individuals with T2DM exhibit decreased endothelial function that is more pronounced in the femoral than in the brachial artery. CFs increase endothelial function not only in the BA but also the FA both in healthy individuals and in those with T2DM who are at increased risk of developing lower extremity PAD and foot ulcers

Age-Dependent Decline in Common Femoral Artery Flow-Mediated Dilation and Wall Shear Stress in Healthy Subjects

Femoral artery (FA) endothelial function is a promising biomarker of lower extremity vascular health for peripheral artery disease (PAD) prevention and treatment; however, the impact of age on FA endothelial function has not been reported in healthy adults. Therefore, we evaluated the reproducibility and acceptability of flow-mediated dilation (FMD) in the FA and brachial artery (BA) (n = 20) and performed cross-sectional FA- and BA-FMD measurements in healthy non-smokers aged 22&ndash;76 years (n = 50). FMD protocols demonstrated similar good reproducibility. Leg occlusion was deemed more uncomfortable than arm occlusion; thigh occlusion was less tolerated than forearm and calf occlusion. FA-FMD with calf occlusion was lower than BA-FMD (6.0 &plusmn; 1.1% vs 6.4 &plusmn; 1.3%, p = 0.030). Multivariate linear regression analysis indicated that age (&minus;0.4%/decade) was a significant independent predictor of FA-FMD (R2 = 0.35, p = 0.002). The age-dependent decline in FMD did not significantly differ between FA and BA (pinteraction agexlocation = 0.388). In older participants, 40% of baseline FA wall shear stress (WSS) values were &lt;5 dyne/cm2, which is regarded as pro-atherogenic. In conclusion, endothelial function declines similarly with age in the FA and the BA in healthy adults. The age-dependent FA enlargement results in a critical decrease in WSS that may explain part of the age-dependent predisposition for PAD