Changes In Microvascular Function Research Articles

Coronary Sinus Reducer Improves Angina, Quality of Life, and CoronaryFlow Reserve in MicrovascularDysfunction.

Coronary microvascular dysfunction (CMD) is a common cause of angina with no obstructive coronary artery disease (ANOCA), and effective treatment options are limited. This study aims to assess the safety and efficacy of the coronary sinus (CS) Reducer (Neovasc, Inc/Shockwave Medical) for treatment of angina in patients with CMD. This Phase II trial enrolled 30 patients with ANOCA, invasively diagnosed CMD, and Canadian Cardiovascular Society (CCS) class 3 to 4 angina despite medical therapy. CMD was defined by coronary flow reserve (CFR)≤2.5 and/or≤50% increase in coronary blood flow (CBF) in response to intracoronary infusion of acetylcholine. Invasive coronary microvascular function testing was performed before and at 120days postimplantation. The primary endpoint was change in microvascular function at 120days. Secondary endpoints were changes in CCS angina class and Seattle Angina Questionnaire (SAQ) scores. Mean age was 54.8 ± 11.0 years; 67% (20/30) were women. In patients with low baseline CFR (endothelium-independent CMD), CFR increased significantly from 2.1 (1.95-2.30) to 2.7 (2.45-2.95) (n=19; P=0.0011). Patients with abnormal CBF response to acetylcholine at baseline (endothelium-dependent CMD) had an increase in CBF response to acetylcholine:-11.0% (-20.15% to 5.85%) to 11.5% (-4.82% to 39.29%) (n=11; P=0.042). There was a significant improvement in CCS angina class from 4.0 (3.25-4.0) to 2.0 (2.0-3.0) (P< 0.001) and increase in each domain of the SAQ questionnaire (P< 0.006 for all). This study demonstrates that the CS Reducer is associated with significant improvement in angina, quality of life, and coronary microvascular function in patients with CMD and may emerge as a novel therapy for patients with ANOCA.

Effects of intracoronary supersaturated oxygen infusion on the time course of myocardial blood flow and extent of microvascular obstruction in an ischemia/reperfusion preclinical swine model

Abstract Introduction Despite successful epicardial reperfusion with primary PCI, reactive changes in microvascular function lead to impaired myocardial reperfusion. Intracoronary SuperSaturated Oxygen Therapy (SSO2) is the only approved therapy that improves myocardial salvage in STEMI pts through the delivery of hyperbaric levels of oxygen to viable ischemic vascular and myocardial cells. Several important questions remain unanswered regarding the potential mechanisms of this benefit. Therefore, the purpose of this study is to determine the effects of SSO2 on the time course of myocardial blood flow (MBF) and the extent of microvascular obstruction (MVO) in an ischemia/reperfusion model. Methods 10 swine (32-40 kg) surviving 90-minute balloon-induced anterior STEMI, and 15-min auto reperfusion, were assigned to 120-min of SSO2 (n=5) or control (n=5) with 120-min auto reperfusion. MBF was evaluated at various time points during the experiment by injection of 15–µm microspheres (BioPal, USA) through a catheter placed in the left ventricle. Before euthanasia, 4% thioflavin-S (TS) was injected into the left anterior descending artery. The left ventricle was sectioned into 10-mm thick slices, and the myocardial rings were photographed under UV light to determine areas at risk (TS positive), MVO (lack of TS staining within TS positive area), and remote zones (contiguous areas unstained by TS). MBF was calculated as the total blood flow within the areas at risk normalized to the total flow within the remote zones. Results All animals experienced significant reduction (p = 0.02) in MBF due to balloon occlusion at the 85-minute MI timepoint compared to baseline (Fig). Following the removal of occlusion, reactive hyperemic flows were observed for both groups at the 15-minute auto reperfusion time point (Fig). Starting at the 30-min time point of autoperfusion to 120-min, the MBF significantly decreased (p=0.02) in the controls (Fig). In contrast during these time points, for the SSO2 group the MBF values were numerically higher than the controls, with average MBF for the SSO2 group being significantly higher (p = 0.03) than the controls (1.1 ± 0.18 vs 0.6 ± 0.13, respectively) at the 120-min timepoint (Fig). MVO was found within the areas at risk in all animals, but the extent of MVO in relation to the area at risk was significantly reduced (p &amp;lt; 0.001) in the SSO2 group versus controls (15.2 ± 7.3% vs 41.8% ± 6.2%, respectively). Conclusions Results from this study showed that in a STEMI swine model, SSO2 prevented reduction in MBF during the 120-min reperfusion period, with significantly increased MBF at the end of the experiment compared to controls. This flow improvement translated to a 64% relative reduction in the extent of MVO compared to controls. These results suggest that one of the mechanisms by which SSO2 improves myocardial salvage may be by limiting early microcirculatory alterations set in motion by a cascade of reduced myocardial flow and MVO.Myocardial Blood Flow vs Time

Follow-up assessment of the microvascular function in patients with long COVID

Long COVID is a complex pathophysiological condition. However, accumulating data suggests that COVID-19 is a systemic microvascular endothelial dysfunction with different clinical manifestations. In this study, a microvascular function was assessed in long COVID patients (n = 33) and healthy controls (n = 30) using flow-mediated skin fluorescence technique (FMSF), based on measurements of nicotinamide adenine dinucleotide fluorescence intensity during brachial artery occlusion (ischemic response, IR) and immediately after occlusion (hyperemic response, HR). Microcirculatory function readings were taken twice, 3 months apart. In addition, we quantified biochemical markers such as the serum L-arginine derivatives and hypoxia-inducible factor 1α (HIF1α) to assess their relation with microvascular parameters evaluated in vivo. In patients with long COVID, serum HIF1α was significantly correlated to IRindex (r = −0.375, p < 0.05). Similarly, there was a significant inverse correlation of serum asymmetric dimethyl-L-arginine levels to both HRmax (r = −0.343, p < 0.05) and HRindex (r = −0.335, p < 0.05). The IR parameters were found lower or negative in long COVID patients and recovered in three-month follow-up. Hypoxia sensitivity value was significantly higher in long COVID patients examined after three months of treatment based on the combination of ACE-inhibitors and beta-adrenolytic compared to baseline condition (85.2 ± 73.8 vs. 39.9 ± 51.7 respectively, p = 0.009). This study provides evidence that FMSF is a sensitive, non-invasive technique to track changes in microvascular function that was impaired in long COVID and recovered after 3 months, especially in patients receiving a cardioprotective therapy.

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old old C57BL/6J mice were treated with saline or CL (β3-adrenergic agonist) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex of aged animals. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in radial arm water maze and Y-maze tests. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of brain microvascular endothelial function and can be potentially repurposed for treating age-associated cognitive decline.

Assessment of hemodynamic indices of conjunctival microvascular function in patients with coronary microvascular dysfunction.

Coronary microvascular dysfunction (CMD) is a cause of ischaemia with non-obstructive coronary arteries (INOCA). It is notoriously underdiagnosed due to the need for invasive microvascular function testing. We hypothesized that systemic microvascular dysfunction could be demonstrated non-invasively in the microcirculation of the bulbar conjunctiva in patients with CMD. Patients undergoing coronary angiography for the investigation of chest pain or dyspnoea, with physiologically insignificant epicardial disease (fractional flow reserve ≥0.80) were recruited. All patients underwent invasive coronary microvascular function testing. We compared a cohort of patients with evidence of CMD (IMR ≥25 or CFR <2.0); to a group of controls (IMR <25 and CFR ≥2.0). Conjunctival imaging was performed using a previously validated combination of a smartphone and slit-lamp biomicroscope. This technique allows measurement of vessel diameter and other indices of microvascular function by tracking erythrocyte motion. A total of 111 patients were included (43 CMD and 68 controls). There were no differences in baseline demographics, co-morbidities or epicardial coronary disease severity. The mean number of vessel segments analysed per patient was 21.0±12.8 (3.2±3.5 arterioles and 14.8±10.8 venules). In the CMD cohort, significant reductions were observed in axial/cross-sectional velocity, blood flow, wall shear rate and stress. The changes in microvascular function linked to CMD can be observed non-invasively in the bulbar conjunctiva. Conjunctival vascular imaging may have utility as a non-invasive tool to both diagnose CMD and augment conventional cardiovascular risk assessment.

Pecan-enriched diet improves cholesterol profiles and enhances postprandial microvascular reactivity in older adults

Pecan-enriched diets have been linked to improved lipid metabolism; however, the impact of pecans on vascular health has yet to be examined. We hypothesized that 4 weeks of a pecan-enriched diet would improve fasting and postprandial blood lipids and vascular function compared with a nut-free diet. In this randomized control study, 44 older adults (59 ± 6 years) consumed 68 g of pecans/d (pecan; n = 21) or avoided all nuts (control; n = 23) for 4 weeks. At pre- and post-diet visits, fasting and postprandial blood lipids, macrovascular (by flow-mediated dilation), and microvascular (tissue saturation index reactive hyperemia [RH] kinetics by continuous-wave near-infrared spectroscopy) function were assessed. From the pre- to post-diet visit, there were greater reductions in fasting total cholesterol (pecan: –14 ± 4.0 vs control: –0.2 ± 5.4 mg/dL; P = .04), low-density lipoprotein (LDL) cholesterol (pecan: –15 ± 3.7 vs control: +1.9 ± 4.4 mg/dL; P = .01), non–high-density lipoprotein cholesterol (pecan: –15 ± 3.6 vs control: –0.5 ± 4.8 mg/dL; P = .02), LDL particle number (pecan: –126 ± 51 vs control: +43 ± 42 nmol/L; P = .01), and LDL medium (pecan: –34 ± 13 vs control: +16 ± 11 nmol/L; P < .01), for pecan vs control. Further, postprandial triglyceride was suppressed for pecan (P = .01) compared with control (P = .78). Postprandial RH slope (P = .04) and RH time to half (P = .004) was different by group, driven by improvements in pecan vs control. However, fasting macro- and microvascular function was unaffected. Daily pecan consumption for 4 weeks improved fasting and postprandial blood lipids and microvascular reactivity in older adults. Because changes in microvascular function typically precipitate macrovascular changes, long-term pecan consumption may improve vascular health and reduce risk for cardiovascular events. This trial was registered at clinicaltrials.gov (NCT04385537).

Comparing the Effects of 30‐ and 60‐min of Acute Whole‐Body Passive Heat Stress on Peripheral Vascular Function in Older Adults

IntroductionMacro‐ and microvascular dysfunction elevate the risk of cardiovascular disease (CVD). Heat therapy has the potential to improve vascular health and reduce CVD risk, but the optimal length of heat stress exposure is unknown. We hypothesized that 1) acute whole body heat stress (WBHS) would increase vascular function and 2) a longer WBHS period (30‐ vs 60‐min) would elicit a greater effect.Methods20 older adults (10 female; 64±7 y) underwent two separate periods of WBHS (30‐ vs 60‐min) via water perfused suit (48°C) in a randomized, counterbalanced design. Macrovascular function via flow‐mediated dilation (FMD) and microvascular function via skin reactive hyperemia (SKBF RH) were assessed before (PRE) and after (POST) WBHS. Core (Tcore; rectal) and skin (Tskin; 6‐site average) temperatures were monitored throughout. Repeated measures ANOVA were used to assess the effect of time (PRE vs POST) and visit (30‐ vs 60‐min) on all outcomes.ResultsTcore and Tskin increased after both WBHS periods (Tcore: 30‐min, PRE: 36.4±0.3, POST: 36.6±0.3°C; 60‐min, PRE: 36.4±0.3, POST: 36.8±0.2°C, p=0.001; Tskin: 30‐min, PRE: 33.5±0.6, POST: 36.3±0.4°C, p&lt;0.0005; 60‐min, PRE: 33.2±0.5°C, POST: 36.6±0.5°C, p&lt;0.0005). FMD% was unchanged (30‐min, PRE: 8.5±5.1%, POST: 7.1±4.2%; 60‐min, PRE: 7.7±3.9%, POST: 6.6±4.3%; p=0.10) after both WBHS periods. During RH, brachial artery shear rate area under the curve was higher after 30‐ (PRE: 17.08±9.57, POST: 26.34±13.06·10‐3 AUC; p=0.003) but not 60‐min (PRE: 21.06±12.30, POST: 27.83±19.32·10‐3 AUC; p=0.186). Total SKBFAUC increased following both 30‐ (PRE: 6.31±3.22, POST: 12.82±6.44·10‐3 AUC; p&lt;0.0005) and 60‐min (PRE: 6.01±3.24, POST: 9.609±4.882·10‐3 AUC; p=0.037), whereas peak SKBF fluxAUC increased following 30‐ (PRE: 1.86±1.54, POST: 4.15±3.07·10‐3 AUC; p=0.001) but not 60‐min (PRE: 1.58±1.31, POST: 2.93±2.77·10‐3 AUC; p=0.1113) of WBHS.DiscussionUp to 60‐min of acute WBHS does not change macrovascular function in older adults. Interestingly, WBHS might increase downstream microvascular functional capacity. The changes in microvascular function following 30‐min of WBHS may reflect early markers of the benefits of repeated whole body heat stress.

Relation of Myocardial Perfusion Reserve and Left Ventricular Ejection Fraction in Ischemic and Nonischemic Cardiomyopathy

Quantification of myocardial perfusion reserve (MPR) using vasodilator stress cardiac magnetic resonance is increasingly used to detect coronary artery disease. However, MPR can also be altered because of changes in microvascular function. We aimed to determine whether MPR can distinguish between ischemic cardiomyopathy (IC) secondary to coronary artery disease and non-IC (NIC) with microvascular dysfunction and no underlying epicardial coronary disease. A total of 60 patients (mean age 65 ± 14 years, 30% women), including 31 with IC and 29 with NIC, were identified from a pre-existing vasodilator stress cardiac magnetic resonance registry. Short-axis cine slices were used to measure left ventricular ejection fraction (LVEF) using the Simpson method of disks. MPR index (MPRi) was determined from first-pass myocardial perfusion images during stress and rest using the upslope ratio, normalized for the arterial input and corrected for rate pressure product. Patients in both groups were divided into subgroups of LVEF ≤35% and LVEF >35%. Differences in MPRi between the subgroups were examined. MPRi was moderately correlated with LVEF in patients with NIC (r=0.53, p=0.03), whereas the correlation in patients with IC was lower (r=0.32, p=0.22). Average LVEF in NIC and IC was 34% ± 8% and 35% ± 8%, respectively (p=0.63). MPRi was not significantly different in IC compared with NIC (1.17 [0.88 to 1.61] vs 1.23 [1.07 to 1.66], p=0.41), including the subgroups of LVEF (IC: 1.20 ± 0.56 vs NIC: 1.15 ± 0.24, p=0.75 for LVEF ≤35% and IC: 1.35 ± 0.44 vs NIC: 1.58 ± 0.50, p=0.19 for LVEF >35%). However, MPRi was significantly lower in patients with LVEF ≤35% compared with those with LVEF>35% (1.17 ± 0.40 vs 1.47 ± 0.47, p=0.01). Similar difference between LVEF groups was noted in the patients with NIC (1.15 ± 0.24 vs 1.58 ± 0.50, p=0.006) but not in the patients with IC (1.20 ± 0.56 vs 1.35 ± 0.44, p=0.42). MPRi can be abnormal in the presence of left ventricular dysfunction with nonischemic etiology. This is a potential pitfall to consider when using this approach to detect ischemia because of epicardial coronary disease using myocardial perfusion imaging.

Reactive hyperaemia augments local heat-induced skin hyperaemia.

What is the central question of this study? It is valuable to be able to monitor disease- or treatment-related changes in the microcirculation. Laser Doppler flowmetry with local heating allows non-invasive monitoring of the skin microcirculation and its ability to vasodilate. Does reactive hyperaemia augment the increase in skin blood flow elicited by local heating? What is the main finding and its importance? The addition of reactive hyperaemia to local heating results in greater vasodilatation than heating alone. Thus, reactive hyperaemia can augment local heat-induced hyperaemia in the skin. The skin circulation has been proposed as a model of generalized microvascular function that could be monitored non-invasively using laser Doppler flowmetry (LDF). The response to heat hyperaemia (HH) is commonly used to monitor disease- or treatment-related changes in microvascular function. We hypothesized that reactive hyperaemia would augment the increase in skin blood flow elicited by local heating. Fourteen healthy young adults were subjected to three different conditions: reactive hyperaemia (RH; skin temperature controlled at 33°C), heat hyperaemia (HH; 42°C held for 40min) and HH+RH. Two Peltier-controlled thermomodules with LDF probes were placed on the right forearm to monitor skin blood flow continuously. A cuff was placed on the right upper arm to elicit RH by inflation to 220mmHg for 5min. This procedure was performed with the skin temperature at 33°C and again after 40min of local heating to 42°C. Beat-by-beat mean arterial pressure (MAP) obtained by a photoplethysmographic sensor on the middle finger of the left hand allowed calculation of cutaneous vascular conductance (CVC) as LDF/MAP. Both HH and RH increased LDF (P<0.0001 and P<0.0001, respectively) and CVC (P=0.0001 and P<0.0001, respectively) above baseline values. The LDF and CVC values were significantly higher during HH+RH when compared with RH or HH alone (P<0.0001). In summary, HH+RH resulted in greater vasodilatation when compared with HH or RH alone. These results indicate that RH can augment local heat-induced hyperaemia in the skin.

The coronary and microcirculatory measurements in patients with aortic valve stenosis study: rationale and design.

Although concomitant coronary artery disease (CAD) is frequent in patients with severe aortic stenosis (AS), hemodynamic assessment of CAD severity in patients undergoing valve replacement for severe AS is challenging. Myocardial hypertrophic remodeling interferes with coronary blood flow and may influence the values of fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). The aim of the current study is to investigate the effect of the AS and its treatment on current indices used for evaluation of CAD. We will compare intracoronary hemodynamics before, immediately after, and 6 mo after aortic valve replacement (AVR) when it is expected that microvascular function has improved. Furthermore, we will compare FFR and resting full-cycle ratio (RFR) with myocardial perfusion single-photon emission-computed tomography (SPECT) as indicators of myocardial ischemia in patients with AS and CAD. One-hundred consecutive patients with AS and intermediate CAD will be prospectively included. Patients will undergo pre-AVR SPECT and intracoronary hemodynamic assessment at baseline, immediately after valve replacement [if transcatheter AVR (TAVR) is chosen], and 6 mo after AVR. The primary end point is the change in FFR 6 mo after AVR. Secondary end points include the acute change of FFR after TAVR, the diagnostic accuracy of FFR versus RFR compared with SPECT for the assessment of ischemia, changes in microvascular function as assessed by the index of microcirculatory resistance (IMR), and the effect of these changes on FFR. The present study will evaluate intracoronary hemodynamic parameters before, immediately after, and 6 mo after AVR in patients with AS and intermediate coronary stenosis. The understanding of the impact of AVR on the assessment of FFR, NHPR, and microvascular function may help guide the need for revascularization in patients with AS and CAD planned for AVR.

Heat Hyperemia or Reactive Hyperemia Alone Do Not Elicit Maximum Skin Blood Flow

The cutaneous circulation has been proposed as a model of generalized microvascular function which could be monitored noninvasively using laser doppler flowmetry. The response to heat hyperemia is commonly used to monitor disease or treatment related changes in microvascular function under the assumption that this represents maximum blood flow. We hypothesized that heat hyperemia alone does not elicit maximum skin blood flow. Purpose To understand how skin blood flow responds to heat hyperemia (HH), reactive hyperemia (RH), and a combination of both stimuli. Methods Ten healthy adults (30 ± 5 years; 74 ± 16.5 kg, mean ± SD) were subjected to 3 different conditions: reactive hyperemia (skin temp controlled at 33°C), heat hyperemia (skin heated to 42°C for 40 minutes), and HH + RH. Two Peltier-controlled thermomodules with laser doppler flow probes were placed on the right forearm to measure skin blood flow. A rapid release cuff on the right upper arm was inflated to 220 mmHg for 5 min to elicit RH while laser doppler flow (LDF) was monitored continuously from 1 min before cuff inflation (baseline) to 3 min after cuff release. This procedure was performed with skin temperature at 33°C and again after 40 min of local heating to 42°C. The mean of the two LDF probes was used in determining the highest 1-sec average skin blood flow for each condition. Beat-by-beat mean arterial pressure (MAP) was obtained by a photoplethysmographic sensor on the middle finger of the left hand. Cutaneous vascular conductance (CVC) was calculated as LDF / MAP. Results Both HH and RH increased LDF and CVC above baseline values (p<0.001). The highest 1-sec LDF and CVC averages were significantly higher during HH+RH when compared to RH or HH (*p < 0.001). Conclusion These results indicate that maximum blood flow and vasodilation are greater during combined heat and reactive hyperemia than during reactive hyperemia or heat hyperemia alone. Future studies should consider using a combination of HH and RH rather than HH alone to assess maximum cutaneous vasodilation.

Weight change and sulfonylurea therapy are related to 3\xa0year change in microvascular function in people with type 2 diabetes

Aims/hypothesisAlthough cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications.MethodsDemographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later.ResultsPeople with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p < 0.001, for those with vs without diabetes, respectively). Similarly, endothelial-independent responses were attenuated in those with diabetes (63.2 [59.2, 67.2] vs 75.1 [67.8, 82.4] AU × min, respectively, p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (pinteraction 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA1c and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI −13.2, 15.7] AU × min in those who lost weight; −15.8 [−10.5, −21.0] AU × min in those with stable weight; and −37.8 [−19.4, −56.2] AU × min in those with weight gain; ptrend < 0.001). This association of weight change with change in endothelial function was driven by people with diabetes; in people without diabetes, the relationship was nonsignificant.Conclusions/interpretationOver 3 years, physiological change in weight was the greatest predictor of change in microvascular function.

Microvascular function in non-dippers: Potential involvement of the salt sensitivity biomarker, marinobufagenin-The African-PREDICT study.

Suppressed nighttime blood pressure dipping is associated with salt sensitivity and may increase the hemodynamic load on the microvasculature. The mechanism remains unknown whereby salt sensitivity may increase the cardiovascular risk of non-dippers. Marinobufagenin, a novel steroidal biomarker, is associated with salt sensitivity and other cardiovascular risk factors independent of blood pressure. The authors investigated whether microvascular function in non-dippers is associated with marinobufagenin. The authors included 220 dippers and 154 non-dippers (aged 20-30years) from the African-PREDICT study, with complete 24-hour urinary marinobufagenin and sodium data. The authors determined dipping status using 24-hour blood pressure monitoring and defined nighttime non-dipping <10%. The authors measured microvascular reactivity as retinal artery dilation in response to light flicker provocation. Young healthy non-dippers and dippers presented with similar peak retinal artery dilation, urinary sodium, and MBG excretion (P>.05). However, only in non-dippers did peak retinal artery dilation relate negatively to marinobufagenin excretion after single (r=-0.20; P=.012), partial (r=-0.23; P=.004), and multivariate-adjusted regression analyses (Adj. R2 =0.34; β=-0.26; P<.001). The authors also noted a relationship between peak artery dilation and estimated salt intake (Adj. R2 =0.30; β=-0.14; P=.051), but it was lost upon inclusion of marinobufagenin (Adj. R2 =0.33; β=-0.015; P=.86). No relationship between microvascular reactivity and marinobufagenin was evident in dippers (P=.77). Marinobufagenin, representing salt sensitivity, may be involved in early microvascular functional changes in young non-dippers and thus contributes to the development of hypertension and cardiovascular disease later in life.

Skeletal Muscle Microvascular Adaptations Following Regular Cold Water Immersion.

This study investigated the effect of endurance training and regular post-exercise cold water immersion on changes in microvascular function. Nine males performed 3 sessions∙wk-1 of endurance training for 4 weeks. Following each session, participants immersed one leg in a cold water bath (10°C; COLD) for 15 min while the contra-lateral leg served as control (CON). Before and after training, microvascular function of the gastrocnemius was assessed using near-infrared spectroscopy, where 5 min of popliteal artery occlusion was applied and monitored for 3 min upon cuff release. Changes in Hbdiff (oxyhemoglobin - deoxyhemoglobin) amplitude (O-AMP), area under curve (O-AUC) and estimated muscle oxygen consumption (mVO2) were determined during occlusion, while the reperfusion rate (R-RATE), reperfusion amplitude (R-AMP) and hyperemic response (HYP) were determined following cuff release. Training increased O-AMP (p=0.010), O-AUC (p=0.011), mVO2 (p=0.013), R-AMP (p=0.004) and HYP (p=0.057). Significant time (p=0.024) and condition (p=0.026) effects were observed for R-RATE, where the increase in COLD was greater compared with CON (p=0.026). In conclusion, R-RATE following training was significantly higher in COLD compared with CON, providing some evidence for enhanced microvascular adaptations following regular cold water immersion.

Krogh's capillary recruitment hypothesis, 100 years on: Is the opening of previously closed capillaries necessary to ensure muscle oxygenation during exercise?

In 1919, August Krogh published his seminal work on skeletal muscle oxygenation. Krogh's observations indicated that muscle capillary diameter is actively regulated, rather than a passive result of arterial blood flow regulation. Indeed, combining a mathematical model with the number of ink-filled capillaries he observed in muscle cross sections taken at different workloads, Krogh was able to account for muscle tissue's remarkably efficient oxygen extraction during exercise in terms of passive diffusion from nearby capillaries. Krogh was awarded the 1920 Nobel Prize for his account of muscle oxygenation. Today, his observations are engrained in the notion of capillary recruitment: the opening of previously closed capillaries. While the binary distinction between "closed" and "open" was key to Krogh's model argument, he did in fact report a continuum of capillary diameters, degrees of erythrocyte deformation, and perfusion states. Indeed, modern observations question the presence of closed muscle capillaries. We therefore examined whether changes in capillary flow patterns and hematocrit among open capillaries can account for oxygen extraction in muscle across orders-of-magnitude changes in blood flow. Our four-compartment model of oxygen extraction in muscle confirms this notion and provides a framework for quantifying the impact of changes in microvascular function on muscle oxygenation in health and disease. Our results underscore the importance of capillary function for oxygen extraction in muscle tissue as first proposed by Krogh. While Krogh's model calculations still hold, our model predictions support that capillary recruitment can be viewed in the context of continuous, rather than binary, erythrocyte distributions among capillaries.NEW & NOTEWORTHY Oxygen extraction in working muscle is extremely efficient in view of single capillaries properties. The underlying mechanisms have been widely debated. Here, we develop a four-compartment model to quantify the influence of each of the hypothesized mechanisms on muscle oxygenation. Our results show that changes in capillary flow pattern and hematocrit can account for the high oxygen extraction observed in working muscle, while capillary recruitment is not required to account for these extraction properties.

6115Influence of microvascular function and coronary flow in the diagnostic precision of resting full-cycle ratio

Abstract Introduction Resting full-cycle ratio (RFR) has been recently described as a non-hyperemic index of coronary stenosis with good concordance with Fractional Flow Reserve (FFR). However, there is no information concerning the influence of microvascular function and coronary flow on RFR results. Purpose To determine if the accuracy of this novel parameter might be influenced by changes in microvascular function. Methods 133 patients admitted in our center between July 2016 and December 2017 underwent coronary physiology study of an angiographically intermediate lesion. 67 subjects presented with AMI and an intermediate lesion in a non-culprit artery, and 66 subjects stable coronary disease. We performed FFR, Coronary Flow Reserve (CFR), Index of Microcirculatory Resistance (IMR) and Resistance Reserve Ratio (RRR) in all of them. We calculated RFR retrospectively from the pressure tracings. Results Coronary physiology parameters showed a non-normal distribution and are presented as median [IQR]: FFR 0.86 [0.79–0.92]; CFR 2.05 [1.4–2.95]; IMR 20.5 [14–32.55]; RRR 2.5 [1.85–3.63]; RFR 0.897 [0.83–0.94]. Patients with abnormal CFR displayed lower RFR values although FFR was not markedly affected (Table 1). These findings remained irrespective of the clinical scenario at presentation. 61 patients had a CFR lower than 2. Correlation between RFR and FFR was not significantly different in patients with abnormal CFR than in those with normal CFR (0,73 vs 0,88; p=0,067) (Figure 1); however, overall binary agreement between RFR and FFR was worse in patients with a low CFR (69% vs 83%; p=0,047). 48 patients had a high IMR (&gt;25). Linear correlation between RFR and FFR was similar in patients with high and normal IMR (0,81 vs 0,83; p=0,784); likewise, binary concordance showed no significant difference between both groups (77% vs 75%, p=0,78). The mean difference between RFR and FFR was 0,025. This was only influenced by CFR: patients with a low CFR had a smaller difference than those with a normal CFR (0,012 vs 0,035; p=0,019). Physiology parameters by CFR group Normal CFR (≥2) Low CFR (&lt;2) P-value FFR 0.88 [0.82–0.93] 0.84 [0.79–0.92] 0.14 RFR 0.91 [0.88–0.95] 0.86 [0.80–0.92] 0.0009 IMR 16.5 [13–27] 25 [16–45.5] 0.002 RRR 3.6 [2.7–4.9] 1.7 [1.3–2.1] &lt;0.0001 Physiological coronary parameters (Median [IQR]) according to CFR. Correlation between RFR and FFR by CFR Conclusion RFR has good overall correlation and concordance with FFR. However, RFR has a lower diagnostic accuracy in patients with a low CFR. Acknowledgement/Funding None

Associations between microvascular function and short-term exposure to traffic-related air pollution and particulate matter oxidative potential.

BackgroundShort-term exposure to ambient air pollution has been associated with acute increases in cardiovascular hospitalization and mortality. However, causative chemical components and underlying pathophysiological mechanisms remain to be clarified. We hypothesized that endothelial dysfunction would be associated with mobile-source (traffic) air pollution and that pollutant components with higher oxidative potential to generate reactive oxygen species (ROS) would have stronger associations.MethodsWe carried out a cohort panel study in 93 elderly non-smoking adults living in the Los Angeles metropolitan area, during July 2012-February 2014. Microvascular function, represented by reactive hyperemia index (RHI), was measured weekly for up to 12 weeks (N = 845). Air pollutant data included daily data from regional air-monitoring stations, five-day average PM chemical components and oxidative potential in three PM size-fractions, and weekly personal nitrogen oxides (NOx). Linear mixed-effect models estimated adjusted changes in microvascular function with exposure.ResultsRHI was inversely associated with traffic-related pollutants such as ambient PM2.5 black carbon (BC), NOx, and carbon monoxide (CO). An interquartile range change increase (1.06 μg/m3) in 5-day average BC was associated with decreased RHI, −0.093 (95 % CI: −0.151, −0.035). RHI was inversely associated with other mobile-source components/tracers (polycyclic aromatic hydrocarbons, elemental carbon, and hopanes), and PM oxidative potential as quantified in two independent assays (dithiothreitol and in vitro macrophage ROS) in accumulation and ultrafine PM, and transition metals.ConclusionsOur findings suggest that short-term exposures to traffic-related air pollutants with high oxidative potential are major components contributing to microvascular dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0157-5) contains supplementary material, which is available to authorized users.

Functional adaptations of the coronary microcirculation to anaemia in fetal sheep.

In fetuses, chronic anaemia stimulates cardiac growth; simultaneously, blood flow to the heart muscle itself is increased, and reserve blood flow capacity of the coronary vascular bed is preserved. Here we examined functional adaptations of the capillaries and small blood vessels responsible for delivering oxygen to the anaemic fetal heart muscle using contrast-enhanced echocardiography. We demonstrate that coronary microvascular flux rate doubled in anaemic fetuses compared to control fetuses, both at rest and during maximal flow, suggesting reduced microvascular resistance consistent with capillary widening. Cardiac fractional microvascular blood volume was not greater in anaemic fetuses, suggesting that growth of new microvascular vessels does not contribute to the increased flow per volume of myocardium. These unusual changes in microvascular function during anaemia may indicate novel adaptive strategies in the fetal heart. Fetal anaemia causes cardiac adaptations that have immediate and life-long repercussions on heart function and health. It is known that resting and maximal coronary conductance both increase during chronic fetal anaemia, but the coronary microvascular changes responsible for the adaptive response are unknown. Until recently, technical limitations have prevented quantifying functional capillary-level adaptations in the in vivo fetal heart. Our objective was to characterise functional microvascular adaptations in chronically anaemic fetal sheep. Chronically instrumented fetuses were randomized to a control group (n=11) or were made anaemic by isovolumetric haemorrhage (n=12) for 1week prior to myocardial contrast echocardiography at 85% of gestation. Anaemia augmented cardiac mass by 23% without changing body weight. In anaemic fetuses, microvascular blood flow per volume of myocardium was twice that of control fetuses at rest, during vasodilatory hyperaemia, and during hyperaemia plus increased aortic pressure. The elevated blood flow was attributable almost entirely to an increase in microvascular blood flux rate whereas microvascular blood volumes were not different between groups at baseline, during hyperaemia, or with hyperaemia plus increased aortic pressure. Increased coronary microvascular flux rate in response to chronic fetal anaemia is consistent with expected reductions in capillary resistance from capillary diameter widening detected in earlier histological studies.

Aerobic Exercise Improves Microvascular Function in Older Adults

PURPOSE: The study aimed to assess changes in microvascular function in older adults following aerobic exercise training. METHODS: Twenty five healthy, sedentary older adults (60-80 years old) participated in a 12-week randomized graded treadmill walking intervention (control (CON), n=12, 66±4 yrs, BMI=30±5; exercise (EX), n=13, 68±6 yrs, BMI=29±5). MRI measured blood-oxygen-level dependent (BOLD) responses of the calf were used to evaluate microvascular function; brief (1s) maximal plantar flexion contractions were performed. Blood flow in the popliteal artery was measured by ultrasound following brief maximal contractions to evaluate small vessel vasodilation in the calf. In addition, muscle oxidative capacity was assessed with 31P MRS following 30-s of plantar flexion. Repeated measures ANOVA was used to assess differences between groups with significance at p <0.05. RESULTS: Peak post-contraction BOLD response in the soleus increased by ~30% in EX (PRE= 103.5±1.4%, POST=104.5±1.6%) compared to CON (PRE: 103.6±1.9%, POST: 103.6±1.7%), p<0.05. Peak post-contraction blood flow in the popliteal artery increased by 20% in EX (PRE: 248±76.8 ml/min, POST: 298±103.9 ml/min) compared to control (PRE: 251±88 ml/min, POST: 259±80 ml/min), p<0.05. Muscle oxidative capacity (tau,s) of the plantar flexors improved by 34% (PRE: 40.2±14.0s, POST: 30.1±10.6s, p<0.05) compared to CON (PRE: 35.4±6.6s, POST: 34.7±9.4s), p<.0.05. CONCLUSION: Aerobic exercise significantly improved BOLD microvascular responses in the soleus of older adults. In addition, peak flow following brief contraction was also improved suggesting increased small vessel vasodilation of the calf. Supported by NIH AG042041.

Effects of short-term walnut consumption on human microvascular function and its relationship to plasma epoxide content

Improved vascular function after the incorporation of walnuts into controlled or high-fat diets has been reported; however, the mechanism(s) underlying this effect of walnuts is(are) poorly defined. The objective of the current study was to evaluate the acute and short-term effects of walnut intake on changes in microvascular function and the relationship of these effects to plasma epoxides, the cytochrome-P450-derived metabolites of fatty acids. Thirty-eight hypercholesterolemic postmenopausal women were randomized to 4 weeks of 5 g or 40 g of daily walnut intake. All outcomes were measured after an overnight fast and 4 h after walnut intake. Microvascular function, assessed as the reactive hyperemia index (RHI), was the primary outcome measure, with serum lipids and plasma epoxides as secondary measures. Compared to 5 g of daily walnut intake, consuming 40 g/d of walnuts for 4 weeks increased the RHI and Framingham RHI. Total cholesterol and low- and high-density cholesterol did not significantly change after walnut intake. The change in RHI after 4 weeks of walnut intake was associated with the change in the sum of plasma epoxides (r=0.65, P=.002) but not with the change in the sum of plasma hydroxyeicosatetraenoic acids. Of the individual plasma epoxides, arachidonic-acid-derived 14(15)-epoxyeicosatrienoic acid was most strongly associated with the change in microvascular function (r=0.72, P<.001). These data support the concept that the intake of walnut-derived fatty acids can favorably affect plasma epoxide production, resulting in improved microvascular function.