Assessing Endothelial Dysfunction Estimating the Differences Between 3 Minute and 5 Minute Reactive Hyperemia

The purpose of this study was to define a lower standard cuff occlusion time to induce reactive hyperemia in assessing endothelial dysfunction. In this study, strong evidence was found by a novel technique that used oscillometric methods, which supported that 3 minute reactive hyperemia was sufficient to elicit a significant difference in arterial compliance from baseline. Twenty healthy Cal Poly students were assessed, (n=12 female, n=8 male) aged 22 years old with a standard deviation of 2.04 years. Arterial compliance was estimated by measuring the peak-to-peak oscillations for baseline, 3 minute reactive hyperemia, and 5 minute reactive hyperemia tests, with the result being statistical evidence of an increase in arterial compliance after 3 minutes of cuff occlusion compared to baseline. The peak-to-peak mean for the 3 minute reactive hyperemia test was significantly greater than the baseline peak-to-peak mean with p-values less than 0.0001. These results support that 3 minute reactive hyperemia is sufficient to assess endothelial dysfunction using oscillometry techniques. Endothelial dysfunction is the most significant predictor of a major adverse cardiovascular event, so this test can be used as an early detection tool for cardiovascular disease and allow patients to find treatment before irreversible damage is done to the body. Implementing this test into routine doctor checkups has the potential to have a significant effect on cardiovascular disease, which is the leading cause of death globally. The currently accepted clinical benchmark performed in hospitals uses high-frequency ultrasound with a standard cuff occlusion time of 5 minutes. Although noninvasive, 5 minutes of cuff occlusion causes slight discomfort to the patient and is not desirable. This test was improved and shortened by using a system based on the oscillometric method of blood pressure measurement. By reducing the duration of the test from 5 minute reactive hyperemia to 3 minute reactive hyperemia, this will make the procedure practical for an increased number of patients, providing a noninvasive option to regularly check for early symptoms of cardiovascular disease

A single serving of blueberry (V. corymbosum) modulates peripheral arterial dysfunction induced by acute cigarette smoking in young volunteers: a randomized-controlled trial

Cigarette smoking causes oxidative stress, hypertension and endothelial dysfunction. Polyphenol-rich foods may prevent these conditions. We investigated the effect of a single serving of fresh-frozen blueberry intake on peripheral arterial function and arterial stiffness in young smokers. Sixteen male smokers were recruited for a 3-armed randomized-controlled study with the following experimental conditions: smoking treatment (one cigarette); blueberry treatment (300 g of blueberry) + smoking; control treatment (300 mL of water with sugar) + smoking. Each treatment was separated by one week of wash-out period. The blood pressure, heart rate, peripheral arterial function (reactive hyperemia and Framingham reactive hyperemia), and arterial stiffness (digital augmentation index, digital augmentation index normalized for a heart rate of 75 bpm) were measured before and 20 min after smoking with Endo-PAT2000. Smoking impaired the blood pressure, heart rate and peripheral arterial function, but did not affect the arterial stiffness. Blueberry consumption counteracted the impairment of the reactive hyperemia index induced by smoking (?\u274.4 ? 0.8% blueberry treatment vs. ?\u2722.0 ? 1.1% smoking treatment, p < 0.01) and Framingham reactive hyperemia (+28.3 ? 19.2% blueberry treatment vs. ?\u2742.8 ? 20.0% smoking treatment, p < 0.0001), and the increase of systolic blood pressure (+8.4 ? 0.02% blueberry treatment vs. +13.1 ? 0.02% smoking treatment, mmHg, p < 0.05) after cigarette smoking. No effect was observed for arterial stiffness and other vital signs. In conclusion, data obtained suggest a protective role of blueberry on reactive hyperemia, Framingham reactive hyperemia, and systolic blood pressure in subjects exposed to smoke of one cigarette. Future studies are necessary to elucidate the mechanisms involved

Endothelial function assessment in atherosclerosis: Comparison of brachial artery flow‑mediated vasodilation and peripheral arterial tonometry

INTRODUCTION Endothelial dysfunction, characterized by the loss of nitric oxide bioavailability, is a key element in the pathogenesis of atherosclerosis and an important prognostic factor in cardiovascular diseases. Therefore, the development of reliable, safe, and noninvasive methods of endothelial function assessment is important for their use in cardiovascular risk stratification. Brachial artery flow‑mediated dilation (FMD) is widely used in research but technical difficulties and problems with calibration between laboratories limit its clinical use. Reactive hyperemia–peripheral artery tonometry (RH‑PAT, EndoPAT) has been developed as a simpler, cheaper, and potentially more reproducible method. OBJECTIVES We aimed to investigate associations between RH‑PAT and FMD in relation to atherosclerotic risk factor profile. PATIENTS AND METHODS The study involved 80 subjects (52 men, 28 women) aged 43.6 ±14.8 years, with moderate‑to‑low cardiovascular risk (mean SCORE, 2.2% ±2%), in whom FMD, RH‑PAT, and intima–media thickness (IMT) were determined. RESULTS The reactive hyperemia index (RHI) measured by RH‑PAT correlated with FMD (r = 0.35, P &lt;0.01). However, no significant correlation was observed between RHI and IMT, SCORE, or the number of classical atherosclerotic risk factors (hypertension, smoking, diabetes, hypercholesterolemia), while FMD was significantly correlated with IMT (r = –0.53, P &lt;0.001), risk factors (r = –0.55, P &lt;0.05), and SCORE (r = –0.4, P &lt;0.05). CONCLUSIONS Despite its technical requirements, FMD is a more sensitive method than RH‑PAT in evaluating the effect of classical atherosclerotic risk factors on vascular endothelial function. Microvasculature response during RH‑PAT needs to be further studied, including the assessment of nonendothelial factors that may affect the measurements, before RH‑PAT becomes the universal tool for the evaluation of the endothelial cells

Modeling Reactive Hyperemia to Better Understand and Assess Microvascular Function: A Review of Techniques

Reactive hyperemia is a well-established technique for the non-invasive evaluation of the peripheral microcirculatory function, measured as the magnitude of limb re-perfusion after a brief period of ischemia. Despite widespread adoption by researchers and clinicians alike, many uncertainties remain surrounding interpretation, compounded by patient-specific confounding factors (such as blood pressure or the metabolic rate of the ischemic limb). Mathematical modeling can accelerate our understanding of the physiology underlying the reactive hyperemia response and guide in the estimation of quantities which are difficult to measure experimentally. In this work, we aim to provide a comprehensive guide for mathematical modeling techniques that can be used for describing the key phenomena involved in the reactive hyperemia response, alongside their limitations and advantages. The reported methodologies can be used for investigating specific reactive hyperemia aspects alone, or can be combined into a computational framework to be used in (pre-)clinical settings

Cutaneous and Muscle Reactive Hyperemia in Young Adults with Major Depressive Disorder

The reactive hyperemic vasodilatory response to a brief period of tissue ischemia provides an index of microvascular function and is an independent predictor of cardiovascular morbidity and mortality. As such, reactive hyperemia is a non-invasive technique that is commonly utilized to provide an index of vascular health in various patient groups. Major depressive disorder (MDD), a non-traditional risk factor for cardiovascular disease (CVD), has been associated with blunted reactive hyperemia, though this is not a universal finding. Further, to date, the quantification of the reactive hyperemic response in adults with MDD has been limited to the forearm muscle, assessed as Doppler ultrasound derived blood velocity in the brachial artery following a period of suprasystolic cuff occlusion. PURPOSE: Here, we sought to more comprehensively assess microvascular reactive hyperemia in otherwise healthy young adults with MDD. We tested the hypothesis that both muscle and cutaneous vasodilation would be blunted in adults with MDD compared to non-depressed young adults. METHODS: Nine healthy adults (HA; age: 22±2 yrs: body mass index: 26.5 ± 1.8 kg/m2) and ten adults with MDD (non-medicated; age: 22±2 yrs: body mass index: 22.6 ± 4.4 kg/m2) participated. Forearm reactive hyperemia was assessed as the increase in blood velocity in the brachial artery following 5-min of suprasystolic cuff occlusion (distal to the olecranon process). In a subset of adults (n=5 HA; n=4 MDD), cutaneous reactive hyperemia was concurrently assessed via laser Doppler flowmetry-derived flux (perfusion units; PU). Peak and total (area-under-the-curve; AUC) reactive hyperemia were quantified for each methodological approach. RESULTS: Neither the brachial artery Doppler ultrasound-derived peak (HA: 1020±383 vs. MDD: 950±239 s-1; p=0.65) nor the total blood flow (HA: 284±77 vs. MDD: 233±153 a.u.; p=0.41) reactive hyperemic response was different between groups. Further, there were no group differences in cutaneous reactive hyperemia (peak: 83±37 HA vs. 79±15 PU MDD, p=0.85; AUC: 8764±2273 HA vs. 8935±1439 a.u. MDD; p=0.90). CONCLUSION: These preliminary data indicate that neither the muscle nor cutaneous vasodilatory response to a brief period of tissue ischemia is blunted in young adults with MDD, suggesting preserved microvascular function

Postconditioning protects against endothelial ischemia-reperfusion injury in the human forearm

Background: Hypoxic cell death follows interruption of blood supply to tissues. Although successful restoration of blood flow is mandatory for salvage of ischemic tissues, reperfusion can paradoxically place tissues at risk of further injury. Brief periods of ischemia applied at the onset of reperfusion have been shown to reduce ischemia-reperfusion (IR) injury, a phenomenon called postconditioning. The aim of this study was to determine whether postconditioning protects against endothelial IR injury in humans, in vivo. Methods and Results: Brachial artery endothelial function was assessed by vascular ultrasound to measure flow-mediated dilation (FMD) in response to forearm reactive hyperemia. FMD was measured before and after IR (20 minutes of arm ischemia followed by 20 minutes of reperfusion) in healthy volunteers. To test the protective effects of postconditioning, 3 cycles of reperfusion followed by ischemia (each lasting 10 or 30 seconds) were applied immediately after 20 minutes of arm ischemia. To determine whether postconditioning needs to be applied at the onset of reperfusion, a 1-minute period of arm reperfusion was allowed before the application of the 10-second postconditioning stimulus. IR caused endothelial dysfunction (FMD 9.1±1.2% pre-IR, 3.6±0.7% post-IR, P<0.001; n=11), which was prevented by postconditioning applied as 10-second cycles of reperfusion/ischemia (FMD 9.9±1.7% pre-IR, 8.3±1.4% post-IR, P=NS; n=11) and 30-second cycles of reperfusion/ischemia (FMD 10.8±1.7% pre-IR, 9.5±1.5% post-IR, P=NS; n=10) immediately at the onset of reperfusion. No protection was observed when the application of the 10-second postconditioning stimulus was delayed for 1 minute after the onset of reperfusion (FMD 9.8±1.2% pre-IR, 4.0±0.9% post-IR, P<0.001; n=8). Conclusions: This study demonstrates for the first time that postconditioning can protect against endothelial IR injury in humans. Postconditioning might reduce tissue injury when applied at the onset of reperfusion by modifying the reperfusion phase of IR

Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis.

BackgroundIndividuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B-cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B-cells, is an effective therapy for RA. The purpose of this study was to determine whether B-cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow-mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients.Methods and resultsRA patients received a single course of rituximab (1000 mg IV infusion at baseline and on day 15). FMD, reactive hyperemia, inflammatory markers, and clinical assessments were performed at baseline, week 12, and week 24. Twenty patients (95% female, median age 54 years) completed the study. Following treatment, FMD improved from a baseline of 4.5±0.4% to 6.4±0.6% at 12 weeks (mean±SE; P&lt;0.0001), followed by a decline at week 24; a similar pattern was observed for hyperemic velocity. Significant decreases in RA disease scores, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, and circulating CD19+ B-cells were sustained through week 24. Cholesterol and triglycerides became significantly although modestly elevated during the study.ConclusionsDepletion of B-cells with rituximab improved macrovascular and microvascular endothelial function and reduced systemic inflammation, despite modest elevation in lipids. Given these results, rituximab should be evaluated in the future for its possible role in reducing excess cardiovascular risk in RA.Clinical trial registrationURL http://ClinicalTrials.gov. Unique identifier: NCT00844714

Peripheral sensory neuropathy is associated with altered postocclusive reactive hyperemia in the diabetic foot

Objective: This study examined whether the presence of peripheral sensory neuropathy or cardiac autonomic deficits is associated with postocclusive reactive hyperemia (reflective of microvascular function) in the diabetic foot. Research design and methods: 99 participants with type 2 diabetes were recruited into this crosssectional study. The presence of peripheral sensory neuropathy was determined with standard clinical tests and cardiac autonomic function was assessed with heart rate variation testing. Postocclusive reactive hyperemia was measured with laser Doppler in the hallux. Multiple hierarchical regression was performed to examine relationships between neuropathy and the peak perfusion following occlusion and the time to reach this peak. Results: Peripheral sensory neuropathy predicted 22% of the variance in time to peak following occlusion (p<0.05), being associated with a slower time to peak but was not associated with the magnitude of the peak. Heart rate variation was not associated with the postocclusive reactive hyperemia response. Conclusions: This study found an association between the presence of peripheral sensory neuropathy in people with diabetes and altered microvascular reactivity in the lower limb

Skeletal Muscle Reactive Hyperemia Is Dependent on the Deoxygenation Stimulus in Young Healthy Humans

Reactive hyperemia tests create mismatches in oxygen (O2 ) delivery and demand by occluding blood flow to skeletal muscle. We tested the hypothesis that skeletal muscle reactive hyperemia is dependent on the specific deoxygenation stimulus. We hypothesized that the magnitude of deoxygenation (Δ=nadir-baseline) would correlate with the magnitude of the reactive hyperemic response (Δ=peak-baseline), whereas the total deoxygenation would correlate with the total reactive hyperemic response. In six (3M:3F) young adults, we continuously measured forearm blood flow using doppler ultrasound on the brachial artery and muscle O2 saturation during three reactive hyperemia tests (1, 5, or 10 minutes in duration). The magnitude of deoxygenation was significantly (P \u3c 0.05 via paired t-test) less during 1 min occlusion (-13±1.6%) compared to 5 min occlusion (-67±14%; P=0.0015) or 10 min occlusion (-74±10%; P=0.0004), but 5 min vs 10 min occlusion were not different (P=0.40). Similarly, the magnitude of the RH was greater in both the 10 min occlusion (329±102 ml/min; P=0.0004) and 5 min occlusion (295±123 ml/min; P=0.005) vs 1 min occlusion (131±69 ml/min; P \u3c 0.0001), but not different from one another (P=0.11). However, total deoxygenation increased progressively from 1 min (-335±51 units), to 5 min (-10732±2209 units), to 10 min (-32357±5053 units; all P \u3c 0.01) as did total reactive hyperemic response (1 min:1326±927 ml; 5 min:7865±4055 ml; 10 min:17447±9698 ml; P \u3c 0.01). These results suggest the reactive hyperemia response is determined by the absolute magnitude of deoxygenation and total difference between O2 supply and demand. Prolonged deoxygenation in the 10 min occlusion led to a greater reactive hyperemia response, potentially mediated by increased muscle metabolite production and greater bioavailability of vasoactive products mediated by fully deoxygenated erythrocytes.https://ecommons.udayton.edu/stander_posters/3838/thumbnail.jp

Remote Ischemic Preconditioning Neither Improves Survival nor Reduces Myocardial or Kidney Injury in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI)

BACKGROUND: Peri-interventional myocardial injury occurs frequently during transcatheter aortic valve implantation (TAVI). We assessed the effect of remote ischemic preconditioning (RIPC) on myocardial injury, acute kidney injury (AKIN) and 6-month mortality in patients undergoing TAVI. METHODS: We performed a prospective single-center controlled trial. Sixty-six patients treated with RIPC prior to TAVI were enrolled in the study and were matched to a control group by propensity-score. RIPC was applied to the upper extremity using a conventional tourniquet. Myocardial injury was assessed using high-sensitive troponin-T (hsTnT), and kidney injury was assessed using serum creatinine levels. Data were compared with the Wilcoxon-Rank and McNemar tests. Mortality was analysed with the log-rank test. RESULTS: TAVI led to a significant rise of hsTnT across all patients (p < 0.001). No significant inter-group difference in maximum troponin release or areas-under-the-curve was detected. Medtronic CoreValve and Edwards Sapien valves showed similar peri-interventional troponin kinetics and patients receiving neither valve did benefit from RIPC. AKIN occurred in one RIPC patient and four non-RIPC patients (p = 0.250). No significant difference in 6-month mortality was observed. No adverse events related to RIPC were recorded. CONCLUSION: Our data do not show a beneficial role of RIPC in TAVI patients for cardio- or renoprotection, or improved survival