Iontophoresis Of Acetylcholine Research Articles

Racial Disparity in Microvascular Function in Men with Newly Diagnosed Prostate Cancer

BACKGROUND:Cardiovascular disease (CVD) is a leading cause of death in men with prostate cancer. In addition, non-Hispanic Black (NHB) men experience worse CVD-related mortality compared to their non-Hispanic White (NHW) counterparts, although the reason for this racial disparity remains unclear. Notably, vascular endothelial dysfunction often precedes the emergence of overt CVD. Indeed, conduit-vessel dysfunction, micro-vascular dysfunction, and arterial stiffness are independent predictors of CVD risk. Thus, the purpose of this study was to comprehensively assess vascular health in recently diagnosed NHB and NHW men with prostate cancer. Methods: Twenty-eight men (10 NHW, 18 NHB) with a new clinical diagnosis of prostate cancer (within 3 months) participated in this study. Flow-mediated dilation (FMD) was performed to represent conduit-vessel vascular endothelial function. Cutaneous post occlusive reactive hyperemia (PORH) with local thermal heating (LTH) and iontophoresis of acetylcholine were performed to represent various mechanisms regulating microvascular function. Lastly, pulse wave velocity (PWV) and pulse wave analysis (PWA) were performed to assess central and aortic stiffness, respectively. Data are reported as mean ± SD. Results: A 4-year age difference ( p=0.131) was observed between NHB (65±7 years) and NHW (69±6 years) men. No differences in BMI or clinical laboratory values were observed between NHB and NHW patients (all p>0.05). NHB men exhibited significantly lower microvascular function compared to NHW men, including PORH (NHB: 117±44 PU vs NHW: 207±47 PU; p<0.001), LTH (NHB: 180±73 PU vs NHW: 281±65 PU; p=0.003), and iontophoresis (NHB: 67±28 PU vs NHW: 136±38 PU; p<0.001). No differences in FMD ( p=0.596), PWV ( p=0.695), or PWA ( p=0.883) were observed between groups. CONCLUSION: The results of the current study provide compelling evidence that microvascular dysfunction is present in NHB men who are recently diagnosed with prostate cancer compared to their NHW counterparts. Given that NHB men were 4 years younger, these data support that the microvascular dysfunction may accelerate vascular aging and contribute to the racial disparity in CVD following prostate cancer diagnosis. Supported by: AHA SFRN 863621 (RAH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Anthocyanins attenuate vascular and inflammatory responses to a high fat high energy meal challenge in overweight older adults: A cross-over, randomised, double-blind clinical trial

Postprandial metabolic imbalances are important indicators of later developing cardiovascular disease (CVD)(1). This study investigated the effects of food anthocyanins on vascular and microvascular function, and CVD associated biomarkers following a high fat high energy (HFHE) meal challenge in overweight older adults. Sixteen subjects (13 female, 3 male, mean age 65.9 SD 6.0 and body mass index 30.6 kg/m 2 SD 3.9) participated in a crossover, randomised, controlled, double-blind clinical trial (Australian New Zealand Clinical Trials Registry # ACTRN12620000437965). Participants consumed a HFHE breakfast meal (65g total fat; 33g saturated fat) together with a 250 mL dose of either intervention (Queen Garnet Plum providing 201 mg anthocyanins) or control (apricot) juice. A wash-out period of 14 days occurred between meal challenges, with a 4-day run-in period for juice consumption before each challenge. Blood samples and blood pressure measures were collected at baseline, 2 h and 4 h following the HFHE meal. Vascular function, assessed using flow mediated dilatation (FMD), and microvascular cutaneous vascular reactivity, measured using Laser Speckle Contrast Imaging (LSCI), were evaluated at baseline and 2 h after the HFHE meal. Participants had a higher 2 h postprandial FMD (+1.14%) and a higher microvascular post-occlusive reactive hyperaemia (+0.10 perfusion units per mmHg) when allocated to the anthocyanin compared to the control arm (P = 0.019 and P = 0.049, respectively). C-reactive protein was lower 4 h postprandially in the anthocyanins (1.80 mg/L, IQR 0.90) vs control arm (2.30 mg/L, IQR 1.95) (P = 0.026), accompanied by a trend for lower concentrations of interleukin-6 (P = 0.075). No significant postprandial differences were observed between treatments for blood pressure, triacylglycerol, total cholesterol, serum derivatives of reactive oxidative metabolites, tumor necrosis factor α, interleukin-1 β, or maximum microvascular perfusion following iontophoresis of acetylcholine. Fruit-based anthocyanins attenuated the potential postprandial detrimental effects of a HFHE challenge on parameters of vascular and microvascular function, and inflammatory biomarkers in overweight older adults. Anthocyanins may reduce cardiovascular risk associated with endothelial dysfunction and inflammatory responses to a typical high fat ‘Western’ meal.

Influence of excessive salt consumption on the functional state of microvascular vessels of the skin of rats with renal dysfunction

Background. Cardiovascular complications are common in chronic kidney disease (CKD). The relationship between the cardiovascular system and the kidneys is complex and diverse, but the question of the mechanisms of the influence of excess NaCl consumption on the functional state of blood vessels during renal dysfunction remains relevant.The aim: to evaluate the effect of a high-salt diet on the functional state of microcirculatory vessels (MCR) of the skin in rats at an early stage of renal dysfunction.Material and Methods. The study was conducted on Wistar rats. The first SO group included animals subjected to sham surgery (SO) and receiving a standard diet (0.34% NaCl); in the second, HS group – animals that also underwent a sham operation, but received a high-salt diet (4% NaCl); in the third, NE group – rats subjected to ¾ nephrectomy (NE) and receiving a standard diet; the fourth, HS+ NE group included rats subjected to ¾ NE and fed a high-salt diet (4% NaCl). Blood pressure (BP) was measured in the tail using the cuff method (Sistola, Russia), MCR was assessed using laser Doppler flowmetry (LDF). The reactivity of skin microvessels was assessed by changes in the MCR index before and after iontophoresis of acetylcholine (ACh) and sodium nitroprusside (NP). Based on the assessment of the spectral characteristics of fluctuations in the MCR index obtained using Wavelet analysis, the value of endothelial, neurogenic and myogenic microvascular tone was calculated.Results. 4 months after ¾ NE, rats showed a decrease in the excretory function of the kidneys. In rats on a highsalt diet, an increase in blood urea levels was noted. The blood pressure in rats of the SO+HS group did not significantly differ from the control animals of the SO group (131 ± 8 and 125 ± 4 mmHg, respectively, NS), NE led to a significant increase in blood pressure (135 ± 5 mmHg in rats of the NE group, and 145 ± 7 mmHg – in the NE+HS group). The average MCR was higher in rats receiving a high-salt diet (SO+HS and NE+HS groups), compared with animals of the corresponding group receiving a standard diet. The combination of NE and high-salt load has an inhibitory effect on the amplitude of fluctuations in the intensity of perfusion in all studied ranges: endothelial, neurogenic and myogenic, while the calculated value of skin microvascular tone in three ranges was the highest in NE+HS group rats. In all experimental groups, the reactivity to AH was reduced compared with the SO group, and after NP iontophoresis, the average perfusion rate significantly decreased only in groups of animals receiving a high-salt diet: SO+HS and NE+HS.Conclusion. A high-salt diet in rats with an initial stage of renal dysfunction contributes to an increase in blood pressure and a decrease in natriuresis compared with animals with NE who received a standard diet. With excessive consumption of table salt in rats after NE, the intensity of cutaneous MCR increases, while reducing the variability of the MCR index. A high-salt diet in rats with NE modifies the characteristics of the spectral components of fluctuations in the MCR index, indicating an increase in tonic effects on skin microvessels in the endothelial, neurogenic and myogenic ranges. With hypernatrial load, animals with ¾ NE have a decrease in the reactivity of cutaneous microvessels to AH and NP, which is mediated by both a decrease in endothelial NO production and a decrease in MMC sensitivity to NO.

Preoperative endothelial dysfunction for the prediction of acute kidney injury after cardiac surgery using cardiopulmonary bypass: a pilot study based on a second analysis of the MONS study

BackgroundUp to 42% of patients develop acute kidney injury (AKI) after cardiac surgery. The aim of this study was to describe the relationship between preoperative microcirculatory function and postoperative AKI after cardiac surgery using cardiopulmonary bypass (CPB).MethodsThe prospective observational cohort MONS enrolled 60 patients scheduled for valvular (n = 30, 50%) or coronary (n = 30, 50%) surgery using CPB. Preoperative microcirculation was assessed during preoperative consultation from January 2019 to April 2019 at the University Hospital of Angers, France, using endothelium-dependent and endothelium-independent reactivity tests on the forearm (iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively). Skin blood flow was measured by laser speckle contrast imaging. The primary endpoint was the occurrence of AKI according to the KDIGO classification during the hospital stay.ResultsForty-three (71.7%) patients developed AKI during the in-hospital follow-up, and 15 (25%) were classified as KDIGO stage 1, 20 (33%) KDIGO stage 2, and 8 (13%) KDIGO stage 3. Regarding preoperative microcirculation, a higher peak amplitude of vasodilation in response to iontophoresis of ACh was found in patients with postoperative occurrence of AKI (35 [20–49] vs 23 [9–44] LSPU, p = 0.04). Iontophoresis of SNP was not significantly different according to AKI occurrence (34 [22–49] vs 36 [20–50] LSPU, p = 0.95). In a multivariable model, the preoperative peak amplitude at iontophoresis of ACh was independently associated with postoperative AKI (OR 1.045 [1.001–1.092], p = 0.045).ConclusionsThe preoperative peak amplitude of endothelium-dependent vasodilation is independently associated with the postoperative occurrence of AKI.Trial registrationClinical-Trials.gov, NCT03631797. Registered 15 August 2018, https://clinicaltrials.gov/ct2/show/NCT03631797

High dietary salt intake attenuates nitric oxide mediated endothelium-dependent vasodilation and increases oxidative stress in pregnancy.

This study aimed to investigate the impact of dietary salt intake during normal pregnancy on maternal microvascular and macrovascular endothelium-dependent reactivity and oxidative stress level. In this cross-sectional study, based on their 24-h urinary sodium excretion, pregnant women (37-40 weeks of gestation) were divided into three groups: normal salt (<5.75 g/day, N = 12), high salt (5.75-10.25 g/day, N = 36), and very high salt (VHS;>10.25 g/day, N = 17). Forearm skin microvascular reactivity in response to vascular occlusion, local heating (LTH) and iontophoresis of acetylcholine (AChID), as well as brachial artery flow mediated dilation (FMD) were measured. Serum nitric oxide, endocan, 8-iso-prostaglandin F2α (8-iso-PGF2α), thiobarbituric acid reactive substances (TBARS), and ferric-reducing ability of plasma assay were measured as biomarkers of endothelial function/activation and oxidative stress. Brachial artery FMD, microvascular AChID, and LTH were significantly decreased in VHS compared with NS group, while LTH was also decreased in normal salt compared with high salt group. Nitric oxide was significantly decreased in both high salt and VHS groups compared with normal salt. Endocan, 8-iso-PGF2α, and TBARS were significantly increased in VHS compared with the normal salt group. High dietary salt intake is associated with decreased nitric oxide mediated endothelium-dependent vasodilation in peripheral microcirculation and macrocirculation of healthy pregnant women due to increased oxidative stress.

Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: Potential role of endothelial dysfunction

Background5-fluorouracil (5-FU) is the second most common cancer chemotherapy associated with short- and long-term cardiotoxicity. Although the mechanisms mediating these toxicities are not well understood, patients often present with symptoms suggestive of microvascular dysfunction. We tested the hypotheses that patients undergoing cancer treatment with 5-FU based chemotherapy regimens would present with impaired microvascular reactivity and that these findings would be substantiated by decrements in endothelial nitric oxide synthase (eNOS) gene expression in 5-FU treated human coronary artery endothelial cells (HCAEC). MethodsWe first performed a cross-sectional analysis of 30 patients undergoing 5-FU based chemotherapy treatment for cancer (5-FU) and 32 controls (CON) matched for age, sex, body mass index, and prior health history (excluding cancer). Cutaneous microvascular reactivity was evaluated by laser Doppler flowmetry in response to endothelium-dependent (local skin heating; acetylcholine iontophoresis, ACh) and -independent (sodium nitroprusside iontophoresis, SNP) stimuli. In vitro experiments in HCAEC were completed to assess the effects of 5-FU on eNOS gene expression. Results5-FU presented with diminished microvascular reactivity following eNOS-dependent local heating compared to CON (P = 0.001). Iontophoresis of the eNOS inhibitor L-NAME failed to alter the heating response in 5-FU (P = 0.95), despite significant reductions in CON (P = 0.03). These findings were corroborated by lower eNOS gene expression in 5-FU treated HCAEC (P < 0.01) compared to control. Peak vasodilation to ACh (P = 0.58) nor SNP (P = 0.39) were different between groups. ConclusionsThe present findings suggest diminished microvascular function along the eNOS-NO vasodilatory pathway in patients with cancer undergoing treatment with 5-FU-based chemotherapy regimens and thus, may provide insight into the underlying mechanisms of 5-FU cardiotoxicity.

Abstract 16797: The Role of Adiposity on Microvascular Dysfunction and Arterial Stiffness in Patients With New Onset Breast Cancer

INTRODUCTION: Increased adiposity is a risk factor for both cardiovascular disease (CVD) and cancer. Microvascular endothelial dysfunction and arterial stiffness are independent risk factors for CVD and can accelerate vascular aging. Whether or not adiposity plays a role in vascular aging over time in patients with new-onset breast cancer (BC) has yet to be elucidated. Hypothesis: Adiposity impacts microvascular dysfunction and arterial stiffness differently in women undergoing therapy for recent BC diagnoses. Methods: Two lean (L; BMI &lt; 25 kg/m 2 ) and four overweight and obese (Ow/Ob; BMI &gt; 25 kg/m 2 ) women diagnosed with BC within the last 3 months participated in the study. Using laser Doppler imaging, microvascular endothelial function was assessed with three protocols: 1) cutaneous post-occlusion reactive hyperemia (PORH), 2) local thermal heating (LTH), and 3) iontophoresis of acetylcholine. Arterial stiffness was assessed using pulse wave velocity (PWV) and pulse wave analysis (PWA). Assessments were made at baseline and at 3 and 6 months following enrollment. Data are reported as means ± SE. Results: No differences in age, height, blood pressure, or total cholesterol (all p &gt;0.05) were observed between L and Ow/Ob groups. Microvascular function and arterial stiffness were similar at baseline between groups. There was a greater decrease in LTH responses from baseline to 6 months post-baseline in Ow/Ob women (Δ-48±4 PU; p =0.001) compared to L women (Δ-16±13 PU; p =0.125). Similar responses in both groups were noted for PORH ( p =0.886) and iontophoresis ( p =0.784). PWV was similar from baseline to 6 months post-baseline in both groups; however, the PWA tended to increase over time in Ow/Ob women (Δ2.5±4.7) and decrease in L women (Δ-3.0±5.0). CONCLUSION: Ow/Ob women have a greater rate of decline in LTH responses compared with L women, whereas similar responses between L and OW/OB women were observed over time for PORH and iontophoresis. In addition, central aortic stiffness increased in Ow/Ob women and decreased in L women, while no change in PWV was observed. These findings suggest that adiposity may impact vascular beds differently over time following the initial diagnosis of breast cancer.

Enhanced Microvascular Adaptation to Acute Physical Stress and Reduced Oxidative Stress in Male Athletes Who Consumed Chicken Eggs Enriched with n-3 Polyunsaturated Fatty Acids and Antioxidants-Randomized Clinical Trial.

This randomized interventional study aimed to determine the effects of n-3 polyunsaturated fatty acids, selenium, vitamin E, and lutein supplementation in the form of enriched chicken egg consumption on microvascular endothelium-dependent vasodilation, oxidative stress, and microvascular response to an acute strenuous training session (ASTS) in competitive athletes. Thirty-one male athletes were assigned to a control (n = 17) or a Nutri4 group (n = 14) who consumed three regular or enriched chicken eggs per day, respectively, for 3 weeks. Significantly enhanced endothelium-dependent responses to vascular occlusion (PORH) and iontophoresis of acetylcholine (AChID) were observed in the Nutri4 group but not in the control group after egg consumption. Formation of peroxynitrite and hydrogen peroxide in peripheral blood mononuclear cells, as well as serum concentration of 8-iso prostaglandin F2α, decreased in the Nutri4 group while remaining unchanged in controls. PORH and AChID were reduced post-ASTS compared with pre-ASTS, both before and after the diets, in both groups. However, the range of PORH responsiveness to ASTS (ΔPORH) increased after consumption of enriched eggs. These results suggest that consumption of enriched chicken eggs has a beneficial effect on microvascular endothelium-dependent vasodilation and the reduction of oxidative stress levels in competitive athletes. Also, microvascular adaptation to the ASTS was improved after consumption of Nutri4 eggs.

Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort

BackgroundMicrovascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association.MethodsWe recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified.ResultsMean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34–165 vs. 46, 27–117 pg/ml) and E/E’(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers.ConclusionsImpaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.

MICROVASCULAR ENDOTHELIUM FUNCTION RESPONSE TO N-3 POLYUNSATURATED FATTY ACIDS, VITAMIN E, SELENIUM AND LUTEIN ENRICHED FUNCTIONAL FOOD IN PATIENTS WITH CHRONIC CORONARY SYNDROME

Objective: Ischemic heart disease is the leading cause of death at a global level. A healthy lifestyle, and especially a healthy diet, can have the effect of reducing the risk of subsequent cardiovascular events and mortality. The aim of this study was to examine the effect of hen eggs enriched with n-3 polyunsaturated fatty acids (n-3 PUFAs), vitamin E, selenium and lutein consumption on oxidative stress level and microvascular endothelium function in patients with existing chronic coronary syndrome (CCS). Design and method: A total of 30 patients (9 women and 21 men) with existing CCS participated in this study. The participants were divided in two groups; Control group (N = 15) who ate three regular hen eggs per day (n-3 PUFAs 146 mg, vitamin E 0.595 mg, selenium 0.0183 mg, lutein 0.11mg/per egg), and Nutri4 group (N = 15) who ate three enriched hen eggs per day (n-3 PUFAs 432 mg, vitamin E 1.098 mg, selenium 0.0191 mg, lutein 0.616 mg/per egg) for three weeks. Peripheral microvascular reactivity in response to vascular occlusion (PORH), and iontophoresis of acetylcholine (AChID) and sodium nitroprusside (SNPID), as well as serum lipid and fatty acids profile, pro- and anti-inflammatory cytokines level, as well as biomarkers of oxidative stress and antioxidant capacity were measured before and after the respective diet protocol. Results: Consumption of Nutri4 eggs significantly decreased serum triglycerides levels and n6/n3 PUFAs ratio, decreased levels of cytokines IL-17A and TGF-1beta, and improved endothelium-dependent microvascular PORH and AChID, but not endothelium-independent response in patients with CCS. Consumption of both Nutri4 and regular hen eggs did not affect biomarkers of oxidative stress and antioxidant capacity in CCS patients. Conclusions: Consumption of hen eggs enriched with n-3 PUFAs, vitamin E, selenium and lutein for three weeks induced an anti-inflammatory response, a favorable effect on lipid and fatty acids profile, especially on triglycerides levels and n6/n3 PUFAs ratio, as well as an improved endothelium-dependent peripheral microvascular reactivity in patients with CCS.

Reversible skin microvascular hyporeactivity in patients with immune-mediated thrombocytopenic thrombotic purpura

BackgroundImmune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by arteriolar and capillary microthrombosis precipitating organ failure. However, the contribution of endothelial dysfunction on impaired microvascular blood flow in iTTP patients has been poorly explored. This pilot observational study aimed to explore endothelial-mediated vasoreactivity in iTTP patients at admission and its changes after plasma exchange therapy (PE).MethodsWe conducted a prospective observational study in patients (> 18-year old) admitted in ICU for iTTP. Using laser Doppler flowmetry and acetylcholine (Ach) iontophoresis in the forearm, we recorded the skin microvascular blood flow and the endothelium-mediated vasoreactivity at admission and after PE. Demographics, biological, clinical courses, and outcomes were also collected. As a control group, we used a previously published cohort of young diabetic patients after correction of ketoacidosis.ResultsEighteen confirmed iTTP patients and 34 controls were included in the study, mainly female (72%) aged 43 ± 16-year-old. At admission, 55% had neurological abnormalities, 50% cardiac issues and 27.8% an acute kidney injury. Median platelet count was 19 G/mL [10–37]. Baseline microvascular blood flow was decreased in iTTP patients when compared to controls (5.97 ± 4.5 vs. 10.1 ± 6.3 PU, P = 0.03), associated with markedly impaired endothelial-mediated skin microvascular reactivity (AUC: 9627 ± 8122 vs. 16,475 ± 11,738, P = 0.03). Microvascular reactivity improved after the first PE session (AUC: 9627 ± 8122 vs 16,558 ± 10,699, P = 0.007, respectively, baseline and post-PE1) and much more after the second session (26,431 ± 23,181, P = 0.04 post-PE1 vs post-PE2). Hemolysis biomarkers (LDH and bilirubin) negatively correlated with skin microvascular flow and vasoreactivity.ConclusionWe highlighted a marked yet reversible skin endothelium-mediated microvascular hyporeactivity in iTTP patients that could participate in organ injury pathophysiology.

The peripheral vascular responses in non-freezing cold injury and matched controls.

What is the central question of this study? Does non-freezing cold injury (NFCI) alter normal peripheral vascular function? What is the main finding and its importance? Individuals with NFCI were more cold sensitive (rewarmed more slowly and felt more discomfort) than controls. Vascular tests indicated that extremity endothelial function was preserved with NFCI and that sympathetic vasoconstrictor response might be reduced. The pathophysiology underpinning the cold sensitivity associated with NFCI thus remains to be identified. The impact of non-freezing cold injury (NFCI) on peripheral vascular function was investigated. Individuals with NFCI (NFCI group) and closely matched controls with either similar (COLD group) or limited (CON group) previous cold exposure were compared (n=16). Peripheral cutaneous vascular responses to deep inspiration (DI), occlusion (PORH), local cutaneous heating (LH) and iontophoresis of acetylcholine and sodium nitroprusside were investigated. The responses to a cold sensitivity test (CST) involving immersion of a foot in 15°C water for 2min followed by spontaneous rewarming, and a foot cooling protocol (footplate cooled from 34°C to 15°C), were also examined. The vasoconstrictor response to DI was lower in NFCI compared to CON (toe: 73 (28)% vs. 91 (17)%; P=0.003). The responses to PORH, LH and iontophoresis were not reduced compared to either COLD or CON. During the CST, toe skin temperature rewarmed more slowly in NFCI than COLD or CON (10min: 27.4 (2.3)°C vs. 30.7 (3.7)°C and 31.7 (3.9)°C, P<0.05, respectively); however, no differences were observed during the footplate cooling. NFCI were more cold-intolerant (P<0.0001) and reported colder and more uncomfortable feet during the CST and footplate cooling than COLD and CON (P<0.05). NFCI showed a decreased sensitivity to sympathetic vasoconstrictor activation than CON and greater cold sensitivity (CST) compared to COLD and CON. None of the other vascular function tests indicated endothelial dysfunction. However, NFCI perceived their extremities to be colder and more uncomfortable/painful than the controls.

Systemic microvascular response to insulin is associated with risk of heart failure with preserved ejection fraction in women with type 2 diabetes

Abstract Background Endothelial microvascular dysfunction (MD) is a key pathophysiologic mechanism for heart failure with preserved ejection fraction (HFpEF). Comorbidities such as type 2 diabetes (T2D) indeed can affect the endothelium of both peripheral and coronary microcirculation, thereby triggering systemic derangements as well as left ventricular diastolic dysfunction (LVDD). Altered microvascular response to insulin is common in T2D but its clinical relevance and association with cardiovascular risk and particularly HFpEF remains unclear. Likewise, the involvement of systemic MD in early HFpEF and LVDD is uncertain. Finally, the influence of sex on MD and on its association with HFpEF needs further investigation to help understand the female predominance in HFpEF. Purpose We aimed to characterize systemic MD in T2D, and investigate its association with clinical and echocardiographic markers of LVDD/HFpEF. Further, we aimed to test for effect modification by sex in the association between MD and LVDD/HFpEF. Methods 152 prospectively enrolled participants (77 men, 75 women) from the Hoorn Diabetes Care System Cohort underwent in vivo evaluation of MD, echocardiography and blood sampling. MD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin (Ins), acetylcholine (ACh) and sodium nitroprusside (SNP). The association between indices of MD and markers of LVDD/HFpEF was assessed by multivariable linear regression analysis adjusted for confounders. LVDD was defined as presence of cardiac structural and functional abnormalities, according to current recommendation. Probability of HFpEF was estimated with the H2PEFF score. Results Mean age was 65±6y, mean HbA1c 7.5±1.2%, 70.6% were asymptomatic. Comorbidity burden and biomarkers did not significantly differ between the sexes. Women had smaller LV mass index (82.8±18.1 vs 99.2±20.3 g/m2) and higher E/E' (13.4±4.4 vs 11.3±2.8) compared to men. Skin perfusion plateau after application of each substance was higher in women than men but no significant differences between sexes were observed in terms of relative perfusion change, calculated as 100% × ([Perfusion plateau − Baseline flow] / Baseline flow) for any of the substances. The relative perfusion change due to Ins was associated with the H2PEFF score, independently of cardiovascular risk factors and cardiovascular drug use (1% increase in perfusion associated to 0.07% decrease of the H2PEFF score). Stratified by sex, this association was present only in women (1% increase in perfusion associated to 0.10% decrease of the H2PEFF score). No significant associations were observed between perfusion change after ACh and SNP and H2PEFF score or between any MD indices and LVDD markers. Conclusions Impaired endothelial-mediated vasodilation in response to insulin confers a higher risk of HFpEF in women with T2D. In vivo measures of systemic MD could represent novel cardiovascular risk markers, for refined risk prediction of HFpEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Young Investigator award grant, Early HFpEF and ShePredicts programs, Hartstichting, The Netherlands.

Young South Asian women in the United Kingdom show evidence of blunted endothelium-dependent dilatation: implications for future cardiovascular disease.

Prevalence of cardiovascular disease (CVD) is higher in South Asians than white Europeans. The offspring of hypertensive parents (OH) have greater risk of hypertension than offspring of normotensive parents (ON). We hypothesized that endothelium-dependent dilatation is already blunted in young South Asians, relative to young white European women, particularly in South Asian OH women. In young white European ON, South Asian ON and OH women (18-25 years old; 10 per group) who were normotensive, we recorded cutaneous perfusion by laser Doppler fluximetry during reactive hyperaemia and iontophoresis of acetylcholine (ACh), before and after inhibiting NO synthesis (NOS) or/and cyclooxygenase (COX). In these and an additional 135 age-matched South Asian and white European women, physical activity and life-style factors were assessed by questionnaire. ACh-evoked dilatation was blunted in young South Asians, relative to white European women. It was attenuated by NOS or COX inhibition in white European ON; by NOS inhibition only in South Asian ON, but not OH women. After combined NOS and COX inhibition, ACh-evoked dilatations were similar to control ACh responses. Similar findings were made for reactive hyperaemia. Questionnaire data indicated young South Asians have lower physical activity levels, fresh fruit and vegetable intake than white European women, South Asian OH being lower than white European ON, or OH women. Endothelium-dependent dilatation is blunted in young South Asians, relative to white European women, especially in South Asian OH in whom NO-dependent and prostaglandin-dependent dilatation is blunted. We suggest improved diet and greater physical activity could be particularly effective in improving endothelium-dependent dilatation and reducing future CVD risk in young South Asian OH women.

Effect of hypertension on microcirculatory disorders in patients with rheumatoid arthritis

Introduction. The presence of endothelial dysfunction contributes to the progression of rheumatoid arthritis (RA) and the development of cardiovascular diseases. However, microcirculatory signs in the combination of RA with hypertension have not been studied enough.Objective – to clarify the contribution of concomitant hypertension in the formation of microcirculatory disorders in patients with RA.Materials and methods. The observational study involved 123 patients of both sexes from 18 to 72 years old (103 – the study group with verified RA, 23 – the control group, representing relatively healthy volunteers). Hypertension occurred in 55.3 % of patients. Laser Doppler flowmetry was performed to assess vasomotor function. Both the initial perfusion parameters were studied with the calculation of the amplitude-frequency spectrum, as well as an occlusive test and a test with acetylcholine iontophoresis. Initial perfusion parameters were studied with time– frequency analysis, an arterial occlusion test and an acetylcholine iontophoresis test were performed.Results. Patients with concomitant hypertension against the background of RA had a more pronounced decrease in the amplitudes of the endothelial (p=0.036) and neurogenic (NC) (p=0.005) components of the spectrum, an increase in respiratory modulation (RM) (p=0.002), as well as a decrease in the reserve of capillary blood flow (p=0.010) and shortened time to perfusion half-restoration (p=0.042) in the occlusion test. However, there were no significant differences between the groups in terms of the acetylcholine iontophoresis test (p≥0.05). The relationship between the RM amplitude and cardiovascular risk (CVR) was established according to the SCORE (ρ=0.269; p=0.022), as well as with systolic (ρ=0.324; p=0.005) and diastolic (ρ=0.234; p=0.045) blood pressure was established. An assessment of the RM amplitude predicted the presence of concomitant hypertension with a sensitivity of 72.5 % and a specificity of 75 % (p=0.001).Conclusion. The presence of concomitant hypertension against the background of RA was associated with more pronounced vasomotor dysfunction, as well as with the presence of venular hypertension (VH), which is the pathogenetic link of hypertension. At the same time, an increase in the amplitude of the RM, which reflects VH, allows it to be used as an early additional prognostic marker for the presence of concomitant hypertension and increased CVR in patients with RA.

Impaired skin microvascular endothelial reactivity in critically ill COVID-19 patients

BackgroundSome clinical and histological studies have reported that SARS-CoV-2 infection may damage the endothelium. However, the impact of this virus on endothelial function in vivo remains poorly characterized. In this single-center pilot observational study, we performed iontophoresis of acetylcholine coupled with Laser doppler to investigate microvascular endothelial reactivity in COVID-19 patients compared to patients with non-COVID-19 bacterial pneumonia (NCBP) patients.ResultsDuring three consecutive months, 32 COVID-19 patients and 11 control NCBP patients with acute respiratory failure were included. The median age was 59 [50–68] and 69 [57–75] years in COVID-19 and NCBP groups, respectively (P = 0.11). There was no significant difference in comorbidities or medications between the two groups, except for body mass index, which was higher in COVID-19 patients. NCBP patients had a higher SAPS II score compared to COVID-19 patients (P < 0.0001), but SOFA score was not different between groups (P = 0.51). Global hemodynamic and peripheral tissue perfusion parameters were not different between groups. COVID-19 patients had significantly lower skin microvascular basal blood flow than NCBP patients (P = 0.02). In addition, endothelium-dependent microvascular reactivity was threefold lower in COVID-19 patients than NCBP patients (P = 0.008).ConclusionsBoth baseline skin microvascular blood flow and skin endothelial-dependent microvascular reactivity were impaired in critically ill COVID-19 patients compared to NCBP patients, despite a lower disease severity score supporting a specific pathogenic role of SARS-CoV-2 on the endothelium.

MATERNAL SALT INTAKE AND MICROVASCULAR ENDOTHELIAL FUNCTION DURING THE THIRD TRIMESTER OF HEALTHY PREGNANCY

Objective: Even in healthy individuals, high-salt (HS) loading leads to endothelial dysfunction, a hallmark of cardiometabolic diseases, independently of the changes in blood pressure (BP). Still, the effect of the amount of daily salt intake during healthy pregnancy on maternal endothelium-dependent vascular reactivity has not yet been investigated. Thus, this study aimed to assess the effect of the amount of daily salt intake during third trimester of pregnancy on maternal microvascular reactivity to stimuli in healthy pregnant women. Design and method: The present study was designed as a cross-sectional study in which all the data for each pregnant woman were obtained at one-time point between 37 and 40 weeks of gestation. Daily salt intake was estimated based on 24-h urinary sodium excretion using appropriate formula [1-g salt (NaCl) = 393.4 mg Na = 17.1 mmol Na]. Microvascular endothelium-dependent vasodilation in response to vascular occlusion (PORH), iontophoresis of acetylcholine (AChID) and local heating (HEAT), as well as endothelium-independent vasodilation in response to iontophoresis of sodium nitroprusside (SNP) was assessed by Laser Doppler flowmetry (LDF). Results: Preliminary results of the present study involve data obtained from 27 healthy pregnant women. According to the amount of daily salt intake, pregnant women were divided in low-salt (LS, &lt; 5 g of salt/day, N = 4), normal-to-high salt (NHS, 5.0–7.5 g of salt/day, N = 12) and high-salt (HS, &gt; 7.5 g of salt/day, N = 11) group. All pregnant women were normotensive, and BP values did not differ between groups. HEAT was significantly lower in HS compared to LS and NHS group, while PORH and AChID tended to be lower in HS compared to LS and NHS group, but without statistical significance. SNPID did not significantly differ between the groups. There was weak to moderate negative correlation between daily salt intake and functional markers of microvascular endothelium-dependent vasodilation (PORH, AChID and HEAT). Conclusions: The amount of daily salt intake significantly affects maternal endothelium-dependent microvascular reactivity during third trimester of healthy pregnancy, i.e. the increased salt intake significantly reduces the endothelium-dependent dilatation of the skin microcirculation, especially responses mediated by nitric-oxide (NO).

FUNCTIONAL FOOD ENRICHED IN N-3 POLYUNSATURATED FATTY ACIDS, SELENIUM, LUTEIN AND VITAMIN E ENHANCES MICROVASCULAR ENDOTHELIAL FUNCTION OF COMPETITIVE ATHLETES

Objective: A substantial proportion of competitive athletes do not reach dietary goals for various macro- and micronutrients, important in creating a favorable oxidative environment, which is one of a principal determinant of normal endothelial function. The present study aimed to determine the effect of functional food consumption enriched in four nutrients (Nutri4) on microvascular endothelium-dependent and endothelium-independent vasodilation of skin microcirculation in competitive athletes. Design and method: Thirty-one competitive athletes were divided to Nutri4 group (N = 17) who ate three n-3 PUFAs, selenium, lutein, and vitamin E enriched hen eggs/daily for 3 weeks (mg per egg: n-3 PUFAs 342, selenium 0.0191, lutein 0.616, vitamin E 1.098), and Control group (N = 14) who ate three regular hens’ eggs/daily (mg per egg: n-3 PUFAs 146, selenium 0.0183, lutein 0.110, vitamin E 0.595). Blood pressure (BP), body mass index (BMI), body composition and serum lipid profile were measured before and after respective dietary protocol. Microvascular endothelium-dependent vasodilation in response to post-occlusive reactive hyperemia (PORH) and iontophoresis of acetylcholine (AChID), and endothelium-independent vasodilation in response to iontophoresis of sodium nitroprusside (SNP) was assessed by Laser Doppler flowmetry (LDF). Results: Mean arterial pressure (MAP) significantly decreased, and BMI, body composition and serum lipid profile remained unchanged following dietary protocol in Nutri4 group, while all variables remained unchanged in Control group. Microvascular PORH (R-O% before 162.6 ± 40.1 vs. after 185.5 ± 63.8, P = 0.050) and AChID (flow increase before 15.6 ± 4.7 vs. after 18.8 ± 5.0, P = 0.045) was significantly increased, while SNPID remained unchanged following dietary protocol in Nutri4 group (flow increase before 15.8 ± 4.9 vs. 14.0 ± 4.2, P = 0.209). In contrast, none was significantly changed in Control group. Conclusions: Consumption of n-3 PUFA, selenium, lutein, and vitamin E enriched functional foods improves peripheral endothelium-dependent microvascular reactivity in competitive athletes, independently of changes in BP and blood lipid concentrations. Importantly, consumption of large amounts of regular hen eggs (3/day for 3 weeks) did not have a detrimental effect on vascular function, BP and serum lipid profiles in athletes.

Skin Blood Flow Responses to Acetylcholine, Local Heating, and to 60% VO2max exercise with and without Nitric Oxide inhibition, in Boys vs. Girls.

To determine sex-related differences in the skin blood flow (SkBF) response to exercise, local heating, and acetylcholine (ACh) in children, and to assess nitric oxide contribution to the SkBF response. Forearm SkBF during local heating (44°C), ACh iontophoresis, and exercise (30-min cycling and 60% of maximum oxygen consumption) was assessed, using laser Doppler fluxmetry, in 12 boys and 12 girls (7-13y old), with and without nitric oxide synthase inhibition, using Nω-nitro-L-arginine methyl ester iontophoresis. Local-heating-induced and ACh-induced SkBF increase were not different between boys and girls (local heating: 1445% [900%] and 1432% [582%] of baseline, P = .57; ACh: 673% [434%] and 558% [405%] of baseline, respectively, P = .18). Exercise-induced increase in SkBF was greater in boys than girls (528% [290%] and 374% [192%] of baseline, respectively, P = .03). Nω-nitro-L-arginine methyl ester blunted the SkBF response to ACh and during exercise (P < .001), with no difference between sexes. SkBF responses to ACh and local heat stimuli were similar in boys and girls, while the increase in SkBF during exercise was greater in boys. The apparent role of nitric oxide was not different between boys and girls. It is suggested that the greater SkBF response in boys during exercise was related to greater relative heat production and dissipation needs at this exercise intensity. The response to body size-related workload should be further examined.

Cutaneous Microvascular Endothelial Function: Effects of Sex and Menopause Stage

BackgroundEndothelial dysfunction and increased arterial stiffness are both associated with increased risk of cardiovascular events and mortality.Vascular aging has been characterized by deteriorating endothelial function accompanied by increasing vascular stiffness that occurs with increasing chronological age, with the onset of these changes varying by sex. Deteriorating large artery vascular function has been reported across the menopause transition in women, but it is unclear if this relationship extends to the cutaneous microvasculature, which may have critical implications for both thermal regulation and general cardiovascular health.Purpose &amp; HypothesisThe primary purpose of this study was to determine the impact of sex and menopausal stage on cutaneous endothelial dependent (EDD) vasodilation. We hypothesized that cutaneous EDD vasodilation would decrease in women in a graded manner across the transition from pre, to peri, to postmenopause with differences compared to age matched men. Secondly, we hypothesized that there would be no differences in cutaneous EDD vasodilation between natural and surgical (i.e., hysterectomy) menopause.MethodsPremenopausal, (n=8, 44±5y), perimenopausal (n=6, 51±2y), and postmenopausal women (n=9, 60±7y) as well as men age matched to the postmenopausal group (n=6, 59±7y) volunteered for this study. Cutaneous EDD vasodilation was measured by local iontophoresis of Acetylcholine (Ach) administration into the forearm vasculature. Red blood cell flux was determined by laser Doppler flowmetry at baseline and after 200µL of Ach. CVC was calculated as the quotient of red blood cell flux and mean arterial pressure and expressed as the percentage increased from baseline (CVC%). Differences were determined using a 1‐way ANOVA. Data are presented as mean ± standard error.ResultsForearm microvascular CVC% was significantly different among groups (P=0.01) after Ach administration. Post hoc analyses revealed an attenuated CVC% response in postmenopausal women (691±150%; P=0.02) and men (733±127%; P=0.05) compared to premenopausal women (1398±247%). There were no differences detected between peri‐ and premenopausal women (1290±140% vs. 1398±247%; P=0.95). Further, we performed a subanalysis in our postmenopausal group which included surgical (n=3) and natural (n=8) postmenopausal women. No differences were present between surgical and natural postmenopausal women (P=0.87), while both the surgical (646±163%; P=0.08) and natural (713±221%; P=0.05) postmenopausal women appeared to have decreased CVC responses compared to premenopausal women (1398±247%).ConclusionsOur findings indicate that cutaneous EDD vasodilation decreases from pre‐ to postmenopause in healthy women. Our data suggests that decreases in microvascular function agrees with reported decrements in large vessel vascular function associated with the menopause transition.