The impact of prediabetes and diabetes on endothelial function in a large population-based cohort.

BACKGROUND: Diabetes and prediabetes are well-recognized risk factors for cardiovascular disease (CVD) and are marked by vascular endothelial dysfunction (ED). However, there is a scarcity of thorough population-based studies examining ED in individuals with diabetes/prediabetes free from manifest CVD. Here, we examined the association between ED assessed by reactive hyperaemia index (RHI) in the finger and diabetes/prediabetes in a large middle-aged population cohort. METHODS: Within the Malmö Offspring Study, following the exclusion of participants <30 years and participants with prevalent CVD, 1384 participants had complete data on all covariates. The RHI was calculated using pulse amplitude tonometry. ED was defined as RHI < 1.67. Multivariable logistic and linear regression models were conducted to investigate associations between ED and RHI with diabetes and prediabetes. RESULTS: The study population had a mean age of 53.6 ± 7.6 years (53% women). In study participants with manifest diabetes (n = 121) and prediabetes (n = 514), ED was present in 42% and 25% respectively, compared to 23% in those with normal glucometabolic status. In multivariable logistic regression analyses, prevalent diabetes was significantly associated with ED (OR 1.95; 95%CI 1.57-3.39; p = 0.002), as well as with lower RHI (ß-coeff. -0.087; p = 0.002). However, prediabetes showed no association with neither ED nor RHI. CONCLUSION: In a population free from CVD, vascular endothelial dysfunction was primarily associated with manifest diabetes, but not with prediabetes, implying that finger ED may develop when diabetes is established, rather than being an early sign of glucose intolerance. Further research is needed to explore whether addressing glucose intolerance could potentially delay or prevent vascular ED onset.

What is the context?Diabetes and prediabetes are known to increase the risk of cardiovascular disease (CVD) through a condition called vascular endothelial dysfunction (ED). However, there is a lack of comprehensive studies on ED in individuals with diabetes/prediabetes who do not already have CVD. In this study, we investigated the association between ED, assessed using the reactive hyperaemia index (RHI) in a finger, and diabetes/prediabetes in a large group of middle-aged individuals.What is new?We conducted this study within the Malmö Offspring Study, involving 1384 participants who were over 30 years old and did not have pre-existing CVD. The average age of the participants was 53 years, with 53% being women. Among those with diagnosed diabetes (121 individuals) and prediabetes (5141 individuals), 42% and 25% respectively showed signs of ED, compared to 23% in those with normal glucose metabolism. In our analyses, we found that established diabetes was significantly associated with ED, as well as with lower finger RHI values. However, prediabetes did not show any significant association with either ED or RHI.What is the impact? In a healthy population without pre-existing CVD, vascular endothelial dysfunction was predominantly linked to diagnosed diabetes, rather than prediabetes. This suggests that ED may develop once diabetes is established, rather than being an early indicator of glucose intolerance. Further research is necessary to investigate whether addressing glucose intolerance could potentially delay or prevent the onset of vascular ED.

Diascopy and histopathological evaluation of nonblanching erythematous dermatoses in dogs.

BACKGROUND: Diascopy is a point-of-care diagnostic test used to differentiate skin erythema due to vascular dilation from haemorrhage. In the veterinary literature, only a handful of diseases have been described to be associated with a negative (nonblanching) diascopy result, and histological investigation of haemorrhage has been inconsistent. OBJECTIVES: Retrospective study to undertake a histopathological investigation of canine, nonblanching erythematous dermatoses for the presence or absence of haemorrhage and vascular changes. MATERIALS AND METHODS: Skin biopsies from dogs presented with moderate-to-severe nonblanching erythema were evaluated histologically. Additionally, clinical data about each patient were analysed. RESULTS: Twenty cases were identified with nonblanching erythema. Diagnoses included vasculopathy (n = 6), canine eosinophilic dermatitis (n = 3), cutaneous epitheliotropic T-cell lymphoma (n = 2), and one case each of sterile granuloma and pyogranuloma syndrome, German shepherd dog pyoderma, multiple mast cell tumours, haemangiosarcoma, exfoliative cutaneous lupus erythematosus, canine leishmaniosis with sebaceous adenitis, sebaceous adenitis with concurrent dermatophytosis, calcinosis cutis and canine atopic dermatitis with insect-bite reaction. One or more vascular changes were present in all 20 cases and included perivascular oedema, endothelial swelling and neutrophilic infiltration of vessel walls. Haemorrhage was identified in 17 of 20 cases (85%). Three cases without dermal haemorrhage were calcinosis cutis, sebaceous adenitis with dermatophytosis and canine atopic dermatitis with insect-bite reaction. CONCLUSIONS AND CLINICAL RELEVANCE: Negative diascopy was associated with haemorrhage and vascular pathological findings in the majority of cases, yet not all. Haemorrhage was identified histologically in all diseases previously reported as nonblanching as well as in a few additional diseases.

Microcirculation dynamics in systemic vasculitis: evidence of impaired microvascular response regardless of cardiovascular risk factors.

OBJECTIVES: Systemic vasculitides (SVs) are a highly inflammatory group of diseases characterized by significant cardiovascular (CV) mortality. Microvascular damage closely linked with accelerated atherosclerosis and thrombosis represents a core pathophysiological mechanism contributing to the excess CV risk of patients with SVs. Skin represents an easily accessible tissue facilitating non-invasive microvascular study. In this study we aimed to investigate microcirculation dynamics and associate them with disease-related factors in patients with SVs. METHODS: We assessed skin microcirculation using laser speckle contrast imaging (LSCI) and vascular reactivity by the post-occlusive reactive hyperaemia (PORH) protocol in a meticulously selected group of patients with SVs without CV disease and compared them to controls, matched for age, sex, BMI and smoking status. RESULTS: Sixty individuals were included in the study, 30 patients and 30 controls. Patients with SVs presented a lower peak magnitude during reperfusion phase (median [interquartile range] 207 [60.1] vs 143.7 [41.0] laser speckle perfusion units, P < 0.001) and lower percentage cutaneous vascular conductance increase (mean (s.d.) 190.0 [49.6]% vs 149.6 [48.9]%, P = 0.002) as compared with controls. Importantly, microvascular damage was correlated with disease duration (P < 0.001, r = -0.563 and P < 0.001, r = 0.442, respectively). CONCLUSION: For the first time we have shown that patients with SVs exhibit impaired microvascular function and blunted reactivity after occlusion, as this was demonstrated by the LSCI technique. Therefore, skin microcirculation may be a useful, non-invasive method in patients with SVs for the early detection of microvascular dysfunction, which is closely related to the high CV risk that these patients bear.

Metabolic and microvascular function assessed using near-infrared spectroscopy with vascular occlusion in women: age differences and reliability.

NEW FINDINGS: What is the central question of this study? Can the near-infrared spectroscopy with vascular occlusion test (NIRS-VOT) reliably measure skeletal muscle metabolic and microvascular function in women? What is the main finding and its importance? The NIRS-VOT can be used as a reliable technique for the assessment of skeletal muscle metabolism and microvascular function in women, with reliability being generally greater in younger women. These findings have important implications for the planning and development of future studies employing the NIRS-VOT in women, and provide insights into the effects of age on these parameters in women specifically. ABSTRACT: We investigated the test-retest reliability of, and age-related differences in, markers of skeletal muscle metabolism and microvascular function derived from the near-infrared spectroscopy with vascular occlusion test (NIRS-VOT) in younger women (YW) and middle-aged and older women (MAOW). Seventeen YW (age 23 ± 4 years) and 17 MAOW (age 59 ± 8 years) completed this study. Participants completed identical experimental visits separated by ∼4 weeks during which the NIRS-VOT was used to quantify the occlusion slope, minimum and maximum tissue saturation, ischaemic index, reperfusion magnitude, the reperfusion and 10-s reperfusion slopes (slope 2 and slope 210-s ), time to max tissue saturation, and area under the reperfusion curve using the local tissue oxygen saturation signal. Except for slope 210-s (intraclass correlation coefficient (ICC) = 0.37; coefficient of variation (CV) = 31%), time to max tissue saturation (ICC = 0.21), and ischaemic index (ICC = 0.37) for MAOW, all of the NIRS variables demonstrated good to excellent relative reliability for the YW (ICCs = 0.74-0.86) and the MAOW (ICCs = 0.51-0.87), with CVs of 2-21% and 2-22%, respectively. The occlusion slope was significantly lower, indicating accelerated deoxygenation, while maximum tissue saturation, reperfusion magnitude, and ischaemic index were significantly higher in YW versus MAOW. No other group differences were found. In conclusion, our data support the use of the NIRS-VOT as a simple, reliable, non-invasive technique for the assessment of peripheral skeletal muscle metabolism and microvascular function in women, with the reliability being generally greater in YW versus MAOW. Further, our data suggest that ageing is associated with lower skeletal muscle metabolism and microvascular hyperaemic responsiveness in women.

Endothelial dysfunction in subfertile women with polycystic ovary syndrome.

RESEARCH QUESTION: Is there an association between post-occlusive reactive hyperaemia (PORH) and ovarian stimulation in women with normoandrogenaemic polycystic ovary syndrome (PCOS)? DESIGN: Women eligible for IVF at an academic fertility centre were invited to join this prospective study. Microvascular endothelial function was measured as PORH by laser Doppler flowmetry (LDF) before and after ovarian stimulation. Metabolic characteristics, hormone profiles and biochemical markers were analysed. RESULTS: Thirty-four normoandrogenaemic women with PCOS and 36 normoandrogenaemic women without PCOS were included. The PCOS group displayed higher C-reactive protein levels and insulin resistance (P = 0.048 and P = 0.025, respectively). No significant difference was found in microcirculatory function between the groups at baseline. After ovarian stimulation, PORH was enhanced in the control group (slope 7.1 ± 3.3 versus 9.7 ± 4.5; P = 0.007; peak flow 30.7 ± 16.3 versus 43.5 ± 17.3, P = 0.008; however, the PCOS group experienced a blunting response to supraphysiological hormone status (slope 8.2 ± 5.1 versus 7.2 ± 4.3, P = 0.212; peak flow, 38.8 ± 19.4 versus 37.0 ± 21.8, P = 0.895). CONCLUSIONS: Impaired microcirculatory function could be found using a non-invasive LDF technique in normoandrogenaemic women with PCOS undergoing IVF, indicating early changes in vascular endothelial dysfunction. Future observational studies should clarify whether PORH measurement might help predict IVF prognosis or obstetric complications.

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer's disease.

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation. Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer's disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer's disease.

The impact of age on endothelial dysfunction measured by peripheral arterial tonometry in a healthy population-based cohort - the Malmö offspring study.

BACKGROUND/AIMS: The reactive hyperaemia index (RHI) assesses endothelial function, with a proposed cut-off of <1.67 for prevalent endothelial dysfunction (ED). However, uncertainties remain about whether this cut-off is age-dependent and applicable in healthy individuals. We aimed to explore ED in relation to age within a large population-based cohort of young to middle-aged, healthy individuals. METHODS: Within the Malmö Offspring Study, a total of 1812 subjects (50.9% women, mean age 48 ± 11 years) were included. Post-occlusion/pre-occlusion ratio of the pulsatile signal amplitudes in the non-dominant upper arm was used to calculate RHI by EndoPat®. ED was defined as RHI < 1.67. Multivariable regression models were used to explore associations between ED and age. RESULTS: Prevalent ED was found in 534 (29.5%) participants. In subjects aged ≤30 years, ED was present in 47.4% compared to 27.6% in subjects ≥30 years (p < 0.001). In multivariable logistic regression analyses, ED was associated with younger age (p < 0.001), higher BMI (p < 0.001) and current smoking (p < 0.001). No sex differences were observed. CONCLUSION: In a large healthy population, RHI < 1.67, an early marker of endothelial dysfunction, was more prevalent in younger individuals, implying that RHI might not be a suitable measure of endothelial function in individuals under 30 years of age. Our findings suggest that low RHI in young, healthy individuals may not necessarily indicate true ED but rather an artefact of the limited ability of young and healthy arteries to dilate post-occlusion. Therefore, the term "pseudo-ED" may be applicable to young individuals with low RHI values.

What is the context?The endothelium is a thin layer of cells that lines the inside of blood vessels, and its proper function is crucial for the maintenance of vascular health. Endothelial dysfunction (ED) is an early marker of cardiovascular disease and is characterised by impaired dilation of blood vessels, which can lead to reduced blood flow and increased risk of heart attacks and strokes. The reactive hyperaemia index (RHI) is a widely used non-invasive test that measures endothelial function by evaluating the dilation of blood vessels in response to temporary occlusion.What is new?This study aimed to investigate the relationship between age and ED in a large population-based cohort of young to middle-aged healthy individuals. The results showed that prevalent ED was more common in younger individuals, with 47.4% of participants aged ≤30 years having ED, compared to 27.6% in those ≥30 years. The study also found that ED was associated with higher BMI and current smoking, but no sex differences were observed.What is the impact?The findings suggest that the proposed RHI cut-off of <1.67 for prevalent ED may not be applicable to individuals under the age of 30, as young and healthy arteries may have limited ability to dilate post-occlusion, resulting in low RHI values that do not necessarily indicate true ED. Therefore, the term "pseudo-ED" may be more appropriate for young individuals with low RHI values.

Global REACH 2018: increased adrenergic restraint of blood flow preserves coupling of oxygen delivery and demand during exercise at high-altitude.

Chronic exposure to hypoxia (high-altitude, HA; >4000 m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signalling restrains skeletal muscle blood flow during handgrip exercise in lowlanders acclimatizing to HA. We tested nine adult males (n = 9) at sea-level (SL; 344 m) and following 21-28 days at HA (∼4300 m). Forearm blood flow (FBF; duplex ultrasonography), mean arterial pressure (MAP; brachial artery catheter), forearm vascular conductance (FVC; FBF/MAP), and arterial and venous blood sampling (O2 delivery ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ ) and uptake ( V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ )) were measured at rest and during graded rhythmic handgrip exercise (5%, 15% and 25% of maximum voluntary isometric contraction; MVC) before and after local α- and ß-adrenergic blockade (intra-arterial phentolamine and propranolol). HA reduced ΔFBF (25% MVC: SL: 138.3 ± 47.6 vs. HA: 113.4 ± 37.1 ml min-1 ; P = 0.022) and Δ V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ (25% MVC: SL: 20.3 ± 7.5 vs. HA: 14.3 ± 6.2 ml min-1 ; P = 0.014) during exercise. Local adrenoreceptor blockade at HA restored FBF during exercise (25% MVC: SLα-ß blockade : 164.1 ± 71.7 vs. HAα-ß blockade : 185.4 ± 66.6 ml min-1 ; P = 0.947) but resulted in an exaggerated relationship between DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ and V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ / V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ slope: SL: 1.32; HA: slope: 1.86; P = 0.037). These results indicate that tonic adrenergic signalling restrains exercise hyperaemia in lowlanders acclimatizing to HA. The increase in adrenergic restraint is necessary to match oxygen delivery to demand and prevent over perfusion of contracting muscle at HA. KEY POINTS: In exercising skeletal muscle, local vasodilatory signalling and sympathetic vasoconstriction integrate to match oxygen delivery to demand and maintain arterial blood pressure. Exposure to chronic hypoxia (altitude, >4000 m) causes a persistent increase in sympathetic nervous system activity that is associated with impaired functional capacity and diminished vasodilatation during exercise. In healthy male lowlanders exposed to chronic hypoxia (21-28 days; ∼4300 m), local adrenoreceptor blockade (combined α- and ß-adrenergic blockade) restored skeletal muscle blood flow during handgrip exercise. However, removal of tonic adrenergic restraint at high altitude caused an excessive rise in blood flow and subsequently oxygen delivery for any given metabolic demand. This investigation is the first to identify greater adrenergic restraint of blood flow during acclimatization to high altitude and provides evidence of a functional role for this adaptive response in regulating oxygen delivery and demand.

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS).

BACKGROUND: Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. METHODS: We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. RESULTS: Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. CONCLUSION: A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

A stronger association of diabetes mellitus with impaired hyperaemia using a novel ECG-gated device compared with peripheral arterial tonometry.

PURPOSE: Impaired digital reactive hyperaemia and flicker-stimulated retinal vascular response are commonly reported risk markers of cardiovascular disease. This is the first study to determine the correlation of these risk markers with diabetes mellitus by comparing our novel flicker-modulated ECG-gated fundoscope with the EndoPAT2000 system. METHODS: In total, 119 controls and 120 participants with diabetes mellitus partook in this cross-sectional study. The EndoPAT2000 system assessed digital reactive hyperaemia under fasting conditions. A mydriatic ECG-gated fundoscope with a novel flicker module acquired digital retinal images of the left eye before, during and after flicker stimulation. An inhouse semi-automated software measured retinal vessel diameters using a validated protocol with two observers repeating measurements in a subset of 10 controls and 10 participants with diabetes mellitus. Intra- and inter-observer reliability analyses occurred by the interclass correlation coefficient. A receiver operating characteristic curve established associations of variables with diabetes mellitus. RESULTS: Diabetes mellitus was more strongly associated with flicker-stimulated retinal arteriolar calibre change from baseline (AUC 0.81, 95% CI 0.75-0.87, p < 0.0001) than reactive hyperaemia index. Median flicker-stimulated arteriolar calibre change from baseline (controls: 2.74%, IQR 1.07 vs diabetes mellitus: 1.64%, IQR 1.25, p < 0.0001) and reactive hyperaemia index (controls: 1.87, IQR 0.81 vs diabetes mellitus: 1.60, IQR 0.81, p = 0.003) were lower in diabetes mellitus than controls. Intra- and inter-observer reliability coefficients were high from 0.87 to 0.93. CONCLUSIONS: Impaired flicker-stimulated retinal arteriolar calibre change from baseline is more highly correlated with diabetes mellitus in this study than a reduced reactive hyperaemia index.

Degree of adiposity and obesity severity is associated with cutaneous microvascular dysfunction in type 2 diabetes.

BACKGROUNDS AND AIMS: Obesity and diabetes independently contribute to cutaneous microvascular dysfunction via pathological processes that are not fully understood. We sought to determine if obesity severity is associated with cutaneous microvascular dysfunction and measures of peripheral arterial disease in adults with type 2 diabetes in cross-sectional observational study design. METHODS AND RESULTS: Primary outcomes were post-occlusive reactive hyperaemia as determined by laser-Doppler fluxmetry (peak flux post-occlusion, time to peak flux post-occlusion, peak as a percentage of baseline, and area under the curve [AuC] index post-occlusion to pre-occlusion). Secondary outcomes were ankle- and toe-brachial indices (ABI and TBI) and systolic toe pressure. Thirty-six participants (20 men, 16 women) with mean age 55 ± 8 years, BMI of 36 ± 5 kg/m2 and duration of diabetes 8 ± 6 years underwent measurements. After adjusting for age and duration of diabetes, SAT and total percentage body fat were able to explain 29% (p = 0.001) and 20% (p = 0.01) of variance of AuC index models, as well as 29% (p = 0.02) and 18% (p = 0.02) of peak as a percentage of baseline models, respectively. Though TBI demonstrated moderate, significant correlations with SAT (r:0.37, p = 0.04) and total percentage body fat (r:0.39, p = 0.03), these were not upheld by regression analyses. Neither ABI nor systolic toe pressure significantly correlated with any measure of adiposity or obesity. CONCLUSION: These findings demonstrate impairment in cutaneous microvascular function related to adiposity and obesity severity in adults with type 2 diabetes, suggesting that obesity may pathologically effect cutaneous microvascular function in the absence of overt macrovascular disease, warranting further investigation.

Similar inflammatory response and conduit artery vascular function between sexes following induced inflammation.

NEW FINDINGS: What is the central question of this study? Are there sex differences in vascular function following induced inflammation when oestrogen is typically similar between sexes? What is the main finding and its importance? The present study suggests no sex differences in conduit artery vascular responses to acutely induced inflammation during the low-oestrogen phase of the menstrual cycle in premenopausal women. However, women exhibit lower microvascular function than men. Overall, the results underpin the role of oestrogen in previously observed sex differences and the importance of reporting the phase in the hormonal cycle when women are studied. ABSTRACT: Sex differences in cardiovascular disease incidence in premenopausal women and age-matched men have been attributed to the cardioprotective influence of oestrogen. However, limited knowledge exists regarding sex differences following acute inflammation when oestrogen concentrations are lower in women. We evaluated sex differences in vascular responses to induced inflammation when oestrogen concentrations are typically lower in women (early follicular phase or placebo phase of hormonal contraception). In 15 women and 14 men, interleukin-6 (IL-6) concentrations and vascular function [via brachial artery flow-mediated dilatation (FMD)] were assessed at baseline (BL) and 24 (24H) and 48 hours (48H) after administration of influenza vaccine. After induction of inflammation, both sexes exhibited an increase in IL-6 concentrations at 24H [mean (SD) BL vs. 24H: women, 0.563 (0.50) vs. 1.141 (0.65) pg/ml; men, 0.385 (0.17) vs. 1.113 (0.69) pg/ml; P < 0.05] that returned to near-baseline concentrations by 48H (BL vs. 48H, P > 0.05). There were no sex differences in FMD, allometrically scaled FMD or IL-6 concentrations at any time point (P > 0.05). Notably, women exhibited significantly lower microvascular function than men at every time point [P < 0.05; reactive hyperaemic area under the curve (in arbitrary units): women, BL 35,512 (14,916), 24H 34,428 (14,292) and 48H 39,467 (13,936); men, BL 61,748 (27,324), 24H 75,028 (29,051) and 48H 59,532 (13,960)]. When oestrogen concentrations are typically lower in women, women exhibit a similar inflammatory response and conduit artery function, but lower microvascular response to reactive hyperaemia, in comparison to age-matched men.

The passive leg movement technique for assessing vascular function: the impact of baseline blood flow.

NEW FINDINGS: What is the central question of this study? The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA): what is the impact of baseline CFA blood flow on the PLM response? What is the main finding and its importance? Although an attenuated PLM response is not an obligatory consequence of increased baseline CFA blood flow, increased blood flow through the deep femoral artery will diminish the response. Care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performing a PLM vascular function assessment. ABSTRACT: The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA). This response is primarily driven by vasodilation of the microvasculature downstream from the deep (DFA) and, to a lesser extent, the superficial (SFA) femoral artery, which facilitate blood flow to the upper and lower leg, respectively. However, the impact of baseline CFA blood flow on the PLM response is unknown. Therefore, to manipulate baseline CFA blood flow, PLM was performed with and without upper and lower leg cutaneous heating in 10 healthy subjects, with blood flow (ultrasound Doppler) and blood pressure (finometer) assessed. Baseline blood flow was significantly increased in the CFA (∼97%), DFA (∼109%) and SFA (∼78%) by upper leg heating. This increase in baseline CFA blood flow significantly attenuated the PLM-induced total blood flow in the DFA (∼62%), which was reflected by a significant fall in blood flow in the CFA (∼49%), but not in the SFA. Conversely, lower leg heating increased blood flow in the CFA (∼68%) and SFA (∼160%), but not in the DFA. Interestingly, this increase in baseline CFA blood flow only significantly attenuated the PLM-induced total blood flow in the SFA (∼60%), and not in the CFA or DFA. Thus, although an attenuated PLM response is not an obligatory consequence of an increase in baseline CFA blood flow, an increase in baseline blood flow through the DFA will diminish the PLM response. Therefore, care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performance of a PLM vascular function assessment.

Young black women demonstrate impaired microvascular but preserved macrovascular function compared to white women.

NEW FINDINGS: What is the central question of this study? Is there a racial disparity in macrovascular and/or microvascular function between young black and white women? What is the main finding and its importance? Black women (BLW) demonstrated impaired microvascular function but similar macrovascular function compared to white women (WHW). These findings suggest an identifiable racial disparity in microvascular function between BLW and WHW as early as young adulthood. Microvascular dysfunction is predictive of future cardiovascular disease (CVD) and generally precedes the development of macrovascular dysfunction. Therefore, these findings also suggest that evaluating microvascular function and CVD risk in young, otherwise healthy BLW are important, as there are known racial disparities in CVD morbidity and mortality in black adults. ABSTRACT: Black women (BLW) have a higher incidence of cardiovascular disease (CVD) morbidity and mortality compared to white women (WHW). Vascular dysfunction is a non-traditional risk factor for CVD and BLW demonstrate impaired vascular function when compared to WHW throughout the lifespan. Several previous studies assessed macrovascular and microvascular function in young BLW compared to WHW, but there has been no recent work exploring this disparity in young women using current, up-to-date methodologies. Therefore, the purpose of this study was to evaluate both macrovascular and microvascular function as assessed by haemodynamic responses to flow-mediated dilatation (FMD), following current FMD guidelines, in young adult BLW and WHW. We hypothesized that BLW would demonstrate attenuated macrovascular and microvascular responses to FMD compared to WHW. Macrovascular function was assessed as the percentage dilatation of the brachial artery following FMD occlusion-cuff release (FMD%). Microvascular function was assessed by total reactive hyperaemia area under the curve (RH-AUC), calculated as the cumulative increase in brachial artery blood flow above baseline following FMD occlusion-cuff release. Participants were tested in the morning hours during the early follicular phase of their menstrual cycle. Twenty-eight young, apparently healthy women completed the study: 17 WHW (23 ± 4 years) and 11 BLW (24 ± 5 years). FMD% was lower in BLW (WHW: 8.0 ± 1.6, BLW: 6.2 ± 2.4%; P = 0.02), but significance was abolished when FMD% was normalized for shear (WHW: 0.1230 ± 0.0388, BLW: 0.1132 ± 0.0405; P = 0.53). RH-AUC was lower in BLW (WHW: 438 ± 133, BLW: 268 ± 66 ml/min; P < 0.001). Young, otherwise healthy BLW demonstrated impaired microvascular function compared to WHW.

Regional variation in nitric oxide-dependent cutaneous vasodilatation during local heating in young adults.

NEW FINDINGS: What is the central question of this study? Are regional differences in nitric oxide (NO)-dependent cutaneous vasodilatation during local skin heating present in young adults? What is the main finding and its importance? NO-dependent cutaneous vasodilatation varied across the body. The abdomen demonstrated larger NO contributions, while the chest demonstrated smaller NO contributions, compared to other regions. This exploratory work is an important first step in characterizing regional heterogeneity of cutaneous microvascular control across the torso and limbs. Equally, it serves to generate hypotheses for future studies examining regional cutaneous microvascular control in ageing and disease. ABSTRACT: Regional variations in cutaneous vasodilatation during local skin heating exist across the body. While nitric oxide (NO) is a well-known modulator of this response, the extent of regional differences in NO-dependent cutaneous vasodilatation during local skin heating remains uncertain. In 16 habitually active young adults (8 females; 25 ± 5 years), cutaneous vascular conductance, normalized to maximum vasodilatation (% CVCmax ), was assessed at the upper chest, abdomen, dorsal forearm, thigh and lateral calf during local skin heating. Across all regions, local skin temperatures were simultaneously increased from 33 to 42°C (1°C per 10 s), and held until a stable heating plateau was achieved (∼40 min). Next, with local skin temperature maintained at 42°C, 20 mM of NG -nitro-l-arginine methyl ester (l-NAME) was continuously infused at each site until a stable l-NAME plateau was achieved (∼40 min). The difference between heating and l-NAME plateaus was identified as the NO contribution for each region. There was no evidence for region-specific responses at baseline (P = 0.561), the heating plateau (P = 0.351) or l-NAME plateau (P = 0.082), but there was for the NO contribution (P = 0.048). Overall, point estimates for between-region differences in the NO contribution varied across the body from 0 to 19% CVCmax . The greatest effects were observed for the abdomen, wherein the NO contribution was consistently greater than for the other regions (range: 9-19% CVCmax ). The chest was consistently lower than the other regions (range: 7-19% CVCmax ). The smallest effects were observed between limb regions (range: 0-2% CVCmax ). These findings advance our understanding of the mechanisms influencing regional variations in the cutaneous vasodilator response to local skin heating in young adults.

Splenic Rhythms and Postprandial Dynamics in Physiology, Portal Hypertension, and Functional Hyposplenism: A Review.

BACKGROUND: Before the discovery of immunological and haematological functions of the spleen, it had for centuries been considered to be a digestive organ of variable size with a role in the portal vein system and nutritional metabolism. In the 19th and 20th centuries, volume changes in the spleen related to nutrition were studied using plethysmographic measurements. Rhythmical and regulatory functions of the spleen were demonstrated in the haemodynamics of the splanchnic region and were described as a "hepatolienal pendulum," a "Windkessel function," or a "pressure compensation." These studies were mainly published in German-speaking countries and have not, as far as is known, been discussed in the English-speaking world so far. SUMMARY: This review explores the historical development of the rhythmical regulatory function of the spleen in the splanchnic region. Older studies and results are followed up in the modern literature, wherever possible, up to the present. The clinical relevance is illustrated with portal hypertension (with congestive or hyperdynamic splenomegaly), coeliac disease, and chronic inflammatory bowel diseases (with functional hyposplenism). Key Message: The spleen's rhythmical regulatory function in nutrition is based on an autonomous rhythm comprising cycles of contractions and dilations of the spleen of around 1 min. These cycles can be influenced by sympathetically mediated single contractions with a release of pooled blood or by portal vein congestion. After food ingestion, the spleen responds either with contraction according to a vasomotor reaction or postprandial congestion with significant increases in volume. The spleen's rhythmical function is lost in the clinical picture of portal hypertension or in coeliac disease and chronic inflammatory bowel diseases. In the aforementioned gastrointestinal diseases, we recommend taking more account of the haemodynamics between the spleen, liver, and intestine. New innovative techniques for recording splenograms are required which, besides elastographic measurements of spleen stiffness, could offer an important tool for early detection, diagnosis, and therapeutic evaluation.

Do skeletal muscle motor units and microvascular units align to help match blood flow to metabolic demand?

PURPOSE: We explore the motor unit recruitment and control of perfusion of microvascular units in skeletal muscle to determine whether they coordinate to match blood flow to metabolic demand. METHODS: The PubMed database was searched for historical, current and relevant literature. RESULTS: A microvascular, or capillary unit consists of 2-20 individual capillaries. Individual capillaries within a capillary unit cannot increase perfusion independently of other capillaries within the unit. Capillary units perfuse a short segment of approx. 12 muscle fibres located beside each other. Motor units consist of muscle fibres that can be dispersed widely within the muscle volume. During a contraction, where not all motor units are recruited, muscle fibre contraction will result in increased perfusion of associated capillaries as well as all capillaries within that capillary unit. Perfusion of the entire capillary unit will result in an increased blood flow delivery to muscle fibres associated with active motor unit plus approximately 11 other inactive muscle fibres within the same region. This will result in an overperfusion of the muscle resulting in blood flow in excess of the muscle fibre needs. CONCLUSIONS: Given the architecture of the capillary units and the dispersed nature of muscle fibres within a motor unit, during submaximal contractions, where not all motor units are recruited, there will be a greater perfusion to the muscle than that predicted by the number of active muscle fibres. Such overperfusion brings into question if blood flow and metabolic demand are as tightly matched as previously assumed.

Regional cutaneous vasodilator responses to rapid and gradual local heating in young adults.

PURPOSE: To examine the extent of regional variations in cutaneous vasodilatation during rapid and gradual local thermal hyperaemia (LTH) in young adults. METHODS: In thirty young adults (21 ± 3 years, 15 females), cutaneous vascular conductance, normalized to maximum local skin heating at 44 °C (%CVCmax), was assessed at the upper chest, abdomen, dorsal arm, dorsal forearm, thigh, and medial calf during rapid (33-42 °C at 1 °C·20 s-1) and gradual (33-42 °C at 1 °C·5 min-1) LTH on separate days. For both protocols, local temperatures were held at 42 °C for up to 35 min, followed by 20-30 min at 44 °C. During rapid LTH, between-region responses were evaluated at baseline, the initial vasodilator peak, and 42 °C plateau. During gradual LTH, responses were assessed at baseline and the 42 °C plateau. RESULTS: There were significant main effects of body region on %CVCmax for the initial peak and plateau during rapid LTH and for the plateau during gradual LTH (all P < 0.001) Conversely, main effects of sex and the sex by region interaction were not significant (all P > 0.05). The magnitudes of between-region differences varied across the body (~1-17% range). The greatest effects were observed for the abdomen, wherein responses were consistently lower compared to other regions. Further, responses were consistent between males and females across all body regions and heating phases. CONCLUSION: Regional variations in the cutaneous vasodilator response to local heating are evident for rapid and gradual LTH in young adults, with the largest effects observed for the abdomen, albeit regional differences were similar between sexes.

Peripheral arterial tonometry as a method of measuring reactive hyperaemia correlates with organ dysfunction and prognosis in the critically ill patient: a prospective observational study.

Predictions of mortality may help in the selection of patients who benefit from intensive care. Endothelial dysfunction is partially responsible for many of the organic dysfunctions in critical illness. Reactive hyperaemia is a vascular response of the endothelium that can be measured by peripheral arterial tonometry (RH-PAT). We aimed to assess if reactive hyperaemia is affected by critical illness and if it correlates with outcomes. Prospective study with a cohort of consecutive patients admitted to an Intensive Care Unit. RH-PAT was accessed on admission and on the 7th day after admission. Early and late survivors were compared to non-survivors. The effect of RH-PAT variation on late mortality was studied by a logistic regression model. The association between RH-PAT and severity scores and biomarkers of organic dysfunction was investigated by multivariate analysis. 86 patients were enrolled. Mean ln(RHI) on admission was 0.580 and was significantly lower in patients with higher severity scores (p < 0.01) and early non-survivors (0.388; p = 0.027). The model for prediction of early-mortality estimated that each 0.1 decrease in ln(RHI) increased the odds for mortality by 13%. In 39 patients, a 2nd RH-PAT measurement was performed on the 7th day. The variation of ln(RHI) was significantly different between non-survivors and survivors (- 24.2% vs. 63.9%, p = 0.026). Ln(RHI) was significantly lower in patients with renal and cardiovascular dysfunction (p < 0.01). RH-PAT is correlated with disease severity and seems to be an independent marker of early mortality, cardiovascular and renal dysfunctions. RH-PAT variation predicts late mortality. There appears to be an RH-PAT impairment in the acute phase of severe diseases that may be reversible and associated with better outcomes.

The Association Between Contrast-Enhanced Ultrasound and Near-Infrared Spectroscopy-Derived Measures of Calf Muscle Microvascular Responsiveness in Older Adults.

BACKGROUND AND AIM: Contrast-enhanced ultrasound (CEUS) measures of post-occlusion skeletal muscle microvascular responsiveness demonstrate the microvascular dysfunction associated with ageing and age-related disease. However, the accessibility of CEUS is limited by the need for intravenous administration of ultrasound contrast agents and sophisticated imaging analysis. Alternative methods are required for the broader assessment of microvascular dysfunction in research and clinical settings. Therefore, we aimed to evaluate the level of association and agreement between CEUS and near-infrared spectroscopy (NIRS)-derived measures of post-occlusion skeletal muscle microvascular responsiveness in older adults. METHODS: During supine rest, participants (n=15, 67±11 years) underwent 5 minutes of thigh cuff-occlusion (200 mmHg). Post-occlusion CEUS measures of calf muscle microvascular responsiveness were made, including time to 95% peak acoustic intensity (TTP95 AI) and the rate of rise (slope AI). Simultaneous measures, including time to 95% peak oxygenated haemoglobin (TTP95 O2Hb) and slope O2Hb, were made using continuous-wave NIRS in the same muscle region. RESULTS: There were strong correlations between TTP95 measures derived from CEUS and NIRS (r=0.834, p=<0.001) and the corresponding measures of slope (r=0.735, p=0.004). The limits of agreement demonstrated by Bland Altman plot analyses for CEUS and NIRS-derived measures of TTP95 (-9.67-1.98 s) and slope (-1.29-5.23%. s-1) were smaller than the minimum differences expected in people with microvascular dysfunction. CONCLUSIONS: The strong correlations and level of agreement in the present study support the use of NIRS as a non-invasive, portable and cost-effective method for assessing post-occlusion skeletal muscle microvascular responsiveness in older adults.