Microvascular Function Research Articles

Retinal vascular changes and arterial stiffness during 8-month isolation and confinement: the SIRIUS-21 space analog mission.

Isolation and confinement are significant stressors during space travel that can impact crewmembers' physical and mental health. Space travel has been shown to accelerate vascular aging and increase the risk of cardiovascular and cerebrovascular disorders. However, the effect of prolonged isolation and confinement on microvascular function has not yet been thoroughly investigated. Retinal vascular imaging was conducted on four crewmembers during- and post-8-month SIRIUS-21 space analog mission. Central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and arteriovenous ratio (AVR) were measured. Pulse wave velocity (PWV), an indicator of arterial stiffness, was also measured. Data from 4 participants was analyzed. These participants had a mean age of 34.75 ± 5.44years, height of 170.00 ± 2.00cm, weight of 74.50 ± 12.53kg, and average BMI of 25.47 ± 3.94kg/m2. During- and post-isolation, average CRVE showed an upward trend (Pearson's r 0.784, R-square 0.62), suggesting a dilation of retinal venules, while AVR showed a downward trend (Pearson's r -0.238, R-square 0.057), which is suggestive of a higher risk of cardiovascular and cerebrovascular dysfunctions. But neither of these trends were statistically significant. Additionally, the average PWV showed an upward trend during- and after-isolation across all crew members. Isolation and confinement appear to contribute towards retinal vascular damage and arterial stiffness. This cautiously suggests an increased risk of cardiovascular and cerebrovascular disorders due to the contribution of the isolation in space flight. Further studies are needed to confirm and expand on these results as we prepare for future manned missions to the Moon and Mars.

Noninvasive assessment of human microvascular function in health and disease using incident dark-field microscopy.

Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.

Interaction of macro- and microvascular function underlies brachial artery flow-mediated dilation in humans.

Brachial artery flow-mediated dilation (BAFMD) is induced by hyperemic wall shear rate (WSR) following forearm ischemia. In older adults, there appears to be a reduced brachial hyperemic WSR and altered stimulus-response relationship compared with young adults. However, it is unclear if an altered forearm microvascular response to ischemia influences brachial hyperemic WSR in older adults. We determined associations between brachial hyperemic WSR and forearm skeletal muscle oxygen saturation in young and older adults. Healthy young (n = 17, 29 ± 7 yr) and older (n = 32, 65 ± 4 yr) adults participated in the study. BAFMD by a multigate spectral Doppler system and forearm skeletal muscle oxygen saturation by near-infrared spectroscopy were concurrently measured. When compared with the young, older adults showed reduced oxygen extraction kinetics (OE, 0.15 [0.12-0.17] vs. 0.09 [0.05-0.12]%s-1) and magnitude (So2deficit, 3,810 ± 1,420 vs. 2,723 ± 1,240%s) during ischemia, as well as oxygen resaturation kinetics (So2slope, 2.5 ± 0.7 vs. 1.7 ± 0.7%s-1) upon reperfusion (all P < 0.05). When OE in the young and So2slope in older adults were stratified by their median values, young adults with OE above the median had greater hyperemic WSR parameters compared with those below the median (P < 0.05), but So2slope in older adults did not show clear differences in hyperemic WSR parameters between those above/below the median. This study demonstrates that, in addition to a reduced microvascular response to ischemia, there may be a dissociation between microvascular response to ischemia and brachial hyperemic WSR in older adults, which may result in a further impairment of BAFMD in this cohort.NEW & NOTEWORTHY Microvascular response to ischemia and subsequent reperfusion is diminished in older adults compared with the young. Furthermore, there appears to be a dissociation between the microvascular response to ischemia and brachial hyperemic WSR in older adults, which may further disturb the BAFMD process in this cohort. A reduced BAFMD in older adults may be a result of multiple alterations occurring both at macro- and microcirculation.

Myocardial Blood Flow Reserve, Microvascular Coronary Health, and Myocardial Remodeling in Patients With Aortic Stenosis.

Coronary microvascular function and hemodynamics may play a role in coronary circulation and myocardial remodeling in patients with aortic stenosis (AS). We aimed to evaluate the relationship between myocardial blood flow and myocardial function in patients with AS, no AS, and aortic valve sclerosis. We included consecutive patients who had resting transthoracic echocardiography and clinically indicated positron emission tomography myocardial perfusion imaging to capture their left ventricular ejection fraction, global longitudinal strain (GLS), and myocardial flow reserve (MFR). The primary outcome was major adverse cardiovascular event (all-cause mortality, myocardial infarction, or late revascularization). There were 2778 patients (208 with aortic sclerosis, 39 with prosthetic aortic valve, 2406 with no AS, and 54, 49, and 22 with mild, moderate, and severe AS, respectively). Increasing AS severity was associated with impaired MFR (P<0.001) and GLS (P<0.001), even when perfusion was normal. Statistically significant associations were noted between MFR and GLS, MFR and left ventricular ejection fraction, and MFR and left ventricular ejection fraction reserve. After a median follow-up of 349 (interquartile range, 116-662) days, 4 (7.4%), 5 (10.2%), and 6 (27.3%) patients experienced a major adverse cardiovascular event in the mild, moderate, and severe AS groups, respectively. In a matched-control analysis, patients with mild-to-moderate AS had higher rates of impaired MFR (52.9% versus 39.9%; P=0.048) and major adverse cardiovascular event (11.8% versus 3.0%; P=0.002). Despite lack of ischemia, as severity of AS increased, MFR decreased and GLS worsened, reflecting worse coronary microvascular health and myocardial remodeling. Positron emission tomography-derived MFR showed a significant independent correlation with left ventricular ejection fraction and GLS. Patients with prosthetic aortic valve showed a high prevalence of impaired MFR.

Inflammation and Myocardial Blood Flow in Cardiac Sarcoidosis.

Cardiac involvement in systemic sarcoidosis or isolated cardiac sarcoidosis plays a pivotal role in the clinical manifestation and prognostication. Active-inflammatory cardiac sarcoidosis is associated with a regional impairment of coronary microvascular function that may confer further detrimental effects on myocardial function needing further characterization. Clinical investigations with cardiac positron emission tomography/computed tomography in conjunction with 18F-fluorodeoxyglucose to determine myocardial inflammation and 13N-ammonia to quantify myocardial blood flow (MBF) in patients with known or suspected cardiac sarcoidosis outlined that sarcoidosis-induced myocardial inflammation was associated with adverse effects on corresponding regional coronary microvascular function. Notably, immune-suppressive treatment caused reductions in myocardial inflammation were paralleled by improvements of coronary microvascular dysfunction outlining direct adverse effect of inflammation on coronary arteriolar function. This review summarizes contributions of cardiac PET imaging in the identification and characterization of active-inflammatory cardiac sarcoidosis, its effect on coronary microvascular function, treatment responses, and prognostic implications.

High-intensity interval training in patients with glaucoma (HIT-GLAUCOMA): protocol for a multicenter randomized controlled exercise trial.

Glaucoma stands as a prominent global cause of irreversible blindness and the primary treatment approach involves reducing intraocular pressure (IOP). However, around one-third of patients exhibit disease progression despite effective IOP reduction. Microvascular endothelial function, chronic inflammation, and oxidative stress are known to affect retinal neuronal networks and have been associated with disease severity and progression. Exercise training has the potential to counteract these mechanisms as add-on treatment to usual care. The HIT-GLAUCOMA study will investigate the effects of a 6-month high-intensity interval training (HIIT) on intermediate endpoints such as local retinal microvascular and systemic large artery function, inflammation, and oxidative stress as well as clinical endpoints such as visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology. The study is a multi-center randomized controlled clinical trial in patients with both normal tension and high-tension primary open angle glaucoma. Across two study centers, 128 patients will be enrolled and randomized on a 1:1 basis into an exercise intervention group and a usual care control group. The primary microvascular endpoints are retinal arteriolar and venular flicker light-induced dilation at 6months. The primary endpoint in the systemic circulation is brachial artery flow-mediated dilation at 6months. We hypothesize that exercise therapy will improve retinal microvascular function and thus ocular blood flow in patients with glaucoma. As clinical outcomes, we will investigate the effect of exercise on visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology. HIT-GLAUCOMA is a blueprint trial design to study the effect of exercise training on neurodegenerative and cardiovascular diseases. Importantly, patients are also expected to benefit from improvements in general health and cardiovascular co-morbidities. If proven effective, exercise may offer a new add-on treatment strategy to slow glaucoma progression. The trial is registered at Clinicaltrials.gov under the identifier NCT06058598 and is currently in the recruitment stage.

The calcineurin-NFATc pathway modulates the lipid mediators in BAL fluid extracellular vesicles, thereby regulating microvascular endothelial cell barrier function.

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse bronchoalveolar lavage fluid (BALF) were analyzed for their lipid mediators by liquid chromatography in conjunction with mass spectrometry (LC-MS/MS). Our data demonstrate that EVs from LPS-treated mice contained significantly higher levels of arachidonic acid (AA) metabolites, which were found in low levels by prior treatment with CNI103. The catalytic activity of lung tissue cytoplasmic phospholipase A2 (cPLA2) increased during ALI, correlating with an increased amount of arachidonic acid (AA) in the EVs. Furthermore, ALI is associated with increased expression of cPLA2, cyclooxygenase 2 (COX2), and lipoxygenases (5-LOX, 12-LOX, and 15-LOX) in lung tissue, and pretreatment with CNI103 inhibited the catalytic activity of cPLA2 and the expression of cPLA2, COX, and LOX transcripts. Furthermore, co-culture of mouse pulmonary microvascular endothelial cell (PMVEC) monolayer and NFAT-luciferase reporter macrophages with BALF EVs from LPS-treated mice increased the pulmonary microvascular endothelial cell (PMVEC) monolayer barrier permeability and luciferase activity in macrophages. However, EVs from CNI103-treated mice had no negative impact on PMVEC monolayer barrier integrity. In summary, BALF EVs from LPS-treated mice carry biologically active NFATc-dependent, AA-derived lipids that play a role in regulating PMVEC monolayer barrier function.

The Influence of Epicardial Resistance on Microvascular Resistance Reserve

BackgroundThe optimal index of microvascular function should be specific for the microvascular compartment. Yet, coronary flow reserve (CFR), despite being widely used to diagnose coronary microvascular dysfunction (CMD), is influenced by both epicardial and microvascular resistance. Conversely, microvascular resistance reserve (MRR) adjusts for fractional flow reserve (FFR), and thus is theoretically independent of epicardial resistance. ObjectivesThe authors tested the hypothesis that MRR, unlike CFR, is not influenced by increasing epicardial resistance, and thus is a more specific index of microvascular function. MethodsIn a cohort of 16 patients who had undergone proximal left anterior descending artery stenting, we created 4 grades of artificial stenosis (no stenosis, mild, moderate, and severe) using a coronary angioplasty balloon inflated to different degrees within the stent. For each stenosis grade, we calculated CFR and MRR using continuous thermodilution (64 measurements of each) to assess their response to changing epicardial resistance. ResultsGraded balloon inflation resulted in a significant sequential decrease in mean FFR (no stenosis: 0.82 ± 0.05; mild: 0.72 ± 0.04; moderate: 0.61 ± 0.05; severe: 0.48 ± 0.09; P < 0.001). This translated into a linear decrease in mean hyperemic coronary flow (no stenosis: 170.5 ± 66.8 mL/min; mild: 149.8 ± 58.8 mL/min; moderate: 124.4 ± 53.0 mL/min; severe: 94.0 ± 45.2 mL/min; P < 0.001). CFR exhibited a marked linear decrease with increasing stenosis (no stenosis: 2.5 ± 0.9; mild: 2.2 ± 0.8; moderate: 1.8 ± 0.7; severe: 1.4 ± 0.6), corresponding to a decrease of 0.3 for a decrease in FFR of 0.1 (P < 0.001). In contrast, MRR exhibited a negligible decrease across all stenosis grades (no stenosis: 3.0 ± 1.0; mild: 3.0 ± 1.0; moderate: 2.9 ± 1.0; severe: 2.8 ± 1.0), corresponding to a decrease of just 0.05 for a decrease in FFR of 0.1 (P < 0.001). ConclusionsMRR, unlike CFR, is minimally influenced by epicardial resistance, and thus should be considered the more specific index of microvascular function. This suggests that MRR can also reliably evaluate microvascular function in patients with significant epicardial disease.

Unveiling the crucial role of intercellular adhesion molecule-1 in secondary diabetic complications.

Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM-1 pathways and to better understand the multifaceted role of ICAM-1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM-1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM-1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM-1 as a key player in their progression. Understanding ICAM-1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM-1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies.

Prognostic Value of Microvascular Resistance Reserve Measured Immediately After PCI in Stable Coronary Artery Disease.

Microvascular resistance reserve (MRR) has been proposed as a specific metric to quantify coronary microvascular function. The long-term prognostic value of MRR measured in stable patients immediately after percutaneous coronary intervention (PCI) is unknown. This study sought to determine the prognostic value of MRR measured immediately after PCI in patients with stable coronary artery disease. This study included 502 patients with stable coronary artery disease who underwent elective PCI and coronary physiological measurements, including pressure and flow estimation using a bolus thermodilution method after PCI. MRR was calculated as coronary flow reserve divided by fractional flow reserve times the ratio of mean aortic pressure at rest to that at maximal hyperemia induced by hyperemic agents. An abnormal MRR was defined as ≤2.5. Major adverse cardiac events (MACEs) were defined as a composite of all-cause mortality, any myocardial infarction, and target-vessel revascularization. During a median follow-up of 3.4 years, the cumulative MACE rate was significantly higher in the abnormal MRR group (12.5 versus 8.3 per 100 patient-years; hazard ratio 1.53 [95% CI, 1.10-2.11]; P<0.001). A higher all-cause mortality rate primarily drove this difference. On multivariable analysis, a higher MRR value was independently associated with lower MACE and lower mortality. When comparing 4 subgroups according to MRR and the index of microcirculatory resistance, patients with both abnormal MRR and index of microcirculatory resistance (≥25) had the highest MACE rate. An abnormal MRR measured immediately after PCI in patients with stable coronary artery disease is an independent predictor of MACE, particularly all-cause mortality.

Microvascular dysfunction associated with reduced nailfold capillary density in patients with ischemia with no obstructive coronary artery disease

Abstract Funding Acknowledgements None. Introduction The impairment of microvascular function present in coronary microcirculation with chronic angina without obstructive coronary arteries. There are insufficient data in the literature regarding possible generalized microangiopathy in this population. Aim The aim of this study is to demonstrate whether patients with Angina with No Obstructive Coronary Artery Disease (ANOCA) compared to individuals without coronary microvascular dysfunction (CMD) are characterized by a different level of nailfold capillaroscopy abnormalities. Methods We examined 18 participants without CMD - non-CMD group [9 female, 50%, mean age: 54.4±8.1 years) and 26 patients with ANOCA - CMD group (22 female, 84,6%, mean age : 53.2±10.7 years). Functional coronary angiography was performed for the assessment of coronary microcirculation in all patients. Coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured in the left anterior descending coronary artery using a temperature/pressure sensor-tipped guidewire. In addition, the assessment of skin microcirculation was performed by capillaroscopy, a non-invasive technique to evaluate small vessels of the microcirculation in the nailfold, using stereomicroscope in all patients. Results In CMD group, mean CFR and IMR were 1.34±0.6 and 44.8±28, respectively. Out of the 26 MVD patients with abnormal CFR, 7 of them (27%) had a normal value of IMR, indicating functional microvascular dysfunction. On the other hand, 18 patients (69%) had an abnormal IMR, indicating structural microvascular dysfunction. Capillary density in patients with MVD was significantly decreased compared to the control group (7.6±2.2 vs 10.9±1.8 vessels/mm, p=0.04). The difference in capillary density between the two groups was statistically significant after adjustment for multiple comparisons (p&amp;lt;0.05). No significant difference was found in body mass index, renal function, medical history of dyslipidemia, diabetes mellitus and smoking status between the two groups (p&amp;lt;0.05). Conclusion Nailfold capillary density was reduced in ANOCA patients compared to control group. These data may provide new insights regarding possible generalized microangiopathy in CMD patients. These results suggest that there is an association between microcirculatory impairment at both heart and peripheral vascular bed level.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

L-Citrulline Supplementation Improves Leg Endothelial Function and Blood Flow Responses to Plantarflexion Exercise in Hypertensive Postmenopausal Women

Menopause and hypertension are associated with macro- and microvascular endothelial dysfunction at rest. Arginine deficiency and low nitric oxide (NO) synthesis may contribute to reduced muscle blood flow (BF) and oxygen delivery to exercising muscles. Improving BF to calf muscles may enhance physical activity. L-Citrulline supplementation (CIT) has improved resting macrovascular endothelial function via increased arginine availability for NO synthesis. Thus, the purpose of this study was to examine the effects of CIT on resting microvascular endothelial function and BF responses to plantarflexion exercise (PFE) in hypertensive postmenopausal women. We hypothesized that CIT would improve microvascular function and BF responses to PFE compared to placebo (PL). Twenty-one hypertensive postmenopausal women were randomized to 4 weeks of CIT (10g/day, n=10) or PL ( n=11). Superficial femoral macro- (flow-mediated dilation; FMD) and microvascular function (5s average peak blood velocity and flow during reperfusion) were assessed by ultrasound at 0 and 4 weeks. Femoral artery BF and vascular conductance (VC) were measured via ultrasound at rest and during 3-minute stages of rhythmic PFE at 5%, 15%, and 30% of 1-repetition maximum (1RM) at 0 and 4 weeks. BF and VC responses to PFE were analyzed as the change from rest to the last minute of each stage. There were no differences between groups in FMD, 5s peak velocity and flow during reperfusion, and vascular responses to PFE at 0 weeks. CIT significantly increased FMD (CIT:Δ1.28 ± 0.42 vs PL:Δ0.01 ± 0.40%, p = 0.04) and 5s peak velocity (CIT:Δ17.44 ± 4.21 vs PL:Δ0.09 ± 4.01 cm/s, p = 0.01) and flow (CIT:Δ220 ± 54 vs PL:Δ35 ± 51 mL/min, p = 0.02) during reperfusion compared to PL. CIT had no effect on BF and VC responses to 5% PFE ( p &gt; 0.05). CIT significantly augmented BF responses to 15% PFE (CIT:Δ82 ± 16 vs PL:Δ22 ± 15 mL/min, p &lt; 0.01) and 30% PFE (CIT:Δ156 ± 33 vs PL:Δ38 ± 32 mL/min, p &lt; 0.01) and VC responses to 15% PFE (CIT:Δ0.80 ± 0.16 vs PL:Δ0.11 ± 0.15 mL*100mmHg/min, p &lt; 0.01) and 30% PFE (CIT:Δ1.49 ± 0.29 vs PL:Δ0.24 ± 0.27 mL*100mmHg/min, p &lt; 0.01) compared to PL. Improvements in FMD were not correlated with BF or VC responses to PFE ( p &gt; 0.05). Improvements in 5s peak velocity were positively correlated with BF responses to 15% PFE ( r = 0.498, p = 0.02) and 30% PFE ( r = 0.532, p = 0.01), and with VC responses to 15% PFE ( r = 0.542, p = 0.01) and 30% PFE ( r = 0.633, p &lt; 0.01). Similarly, augmented 5s flow was positively correlated with BF ( r = 0.461, p = 0.04) and VC ( r = 0.558, p = 0.01) responses to 30% PFE. These findings indicate that CIT improved superficial femoral artery macro- and microvascular endothelial function at rest. However, only improvements in microvascular endothelial function influenced vascular function during leg exercise in hypertensive postmenopausal women. 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.

Central and peripheral cardiovascular responses after acute dietary nitrate supplementation in post-menopausal women

The transition to menopause is accompanied by augmented cardiovascular disease risk, partially attributed to reduced nitric oxide (NO) bioavailability. Despite a lower arterial stiffness than men, postmenopausal women are susceptible to increased aortic pulsatile hemodynamic load because of greater pressure wave reflection and vascular dysfunction. Increasing bioavailable NO with dietary nitrate has shown promise to reduce aortic (aSBP) and brachial (bSBP) systolic pressure healthy postmenopausal women. However, there are limited reports comparing hypertensive (HTN) and normotensive (NTN) postmenopausal women regarding wave separation analysis and vascular function following dietary nitrate supplementation. This study investigated if acute dietary nitrate supplementation would improve aortic hemodynamics, wave reflection characteristics, vascular stiffness, and vasodilatory function. We hypothesized that dietary nitrate would lower pulse wave velocity in hypertensives, lower aortic and brachial blood pressures and forward and backward wave magnitude and increase microvascular, but not macrovascular function in both groups. Fourteen postmenopausal women (n=7 HTN; n=7 NTN) participated in a two-day randomized crossover study design with dietary nitrate (nitrate rich, NR) or a placebo control (NP). Central and peripheral hemodynamics and carotid-femoral pulse wave velocity (cfPWV) were performed with a SphygmoCOR Excel, simultaneous resting macro- and- microvascular function was assessed using flow-mediated vasodilation (FMD) and post occlusive reactive hyperemia (PORH) using near-infrared spectroscopy. aSBP was reduced significantly following NR supplement within groups (HTN: NP 126±2 NR 120±1mmHg) and NTN group (NP 110± 1 NR 104±3mmHg p&lt;0.05). Forward pulse height HTN (NP 29±1.4 NR 26.3±1.4mmHg) NTN (NP 25.6±0.9 NR 24±2.7mmHg) and reflected pulse height HTN (NP 18.2±0.08 NR 17.2±0.4mmHg) NTN (NP 17.7±0.2 NR 15.7±1.07mmHg) were not different. cfPWV was faster in the HTN group and slowed with a NR supplement (HTN: NP 8.2±0.29 NR 7.4±0.31m/s; NTN NP 7.1±0.23 NR 6.6±0.62m/s p&lt;0.05). A significant interaction for %FMD was found (HTN: NP 7.3±0.8 NR 6.2±0.8%; NTN NP 6.6±0.7 NR 9.4±0.7%). Further, we found no difference in the NIRS derived microvascular function measurements (HTN: NP 1.9±0.2 NR 1.7±0.3%/s; NTN NP 1.6±0.1 NR 1.4±0.2%/s p&gt;0.05). These data indicate that dietary nitrate consumption led to a substantial reduction in aortic hemodynamics and reduced pulse wave velocity regardless of hypertension status. Interestingly, macrovascular, but not microvascular vasodilatory function was improved in the NTN women only. Dietary nitrate supplementation appears to have differential effects when considering HTN and NTN postmenopausal women. Supported with funds from The University of Wisconsin-La Crosse RSEL graduate grant. 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.

Mitochondrial and Microvascular Impairments in a Novel Swine Model of Peripheral Artery Disease

Introduction: Impaired skeletal muscle mitochondria and microvascular function have been reported in human peripheral artery disease (PAD). However, no large animal models of PAD have mimicked these impairments. Purpose: The purpose of this study was to examine the skeletal muscle microvasculature and mitochondria in a novel swine model of PAD. Hypothesis: We hypothesized that hindlimb ischemia leads to dysfunction of skeletal muscle microvessels and mitochondria. Methods: Ossabaw swine (n=5) with metabolic syndrome underwent endovascular coil occlusion of the right external iliac artery to generate hindlimb ischemia (ISC). The left leg served as a non-ischemic control (CON). After 4-weeks, biopsies were collected from both legs (lateral gastrocnemius). Skeletal muscle arterioles were assessed using video microscopy. Microvascular vasodilatory function was assessed in response to flow (Shear stress), acetylcholine (ACh), and sodium nitroprusside (SNP). Skeletal muscle mitochondrial function was assessed using high-resolution respirometry. Substrates were administered as follows: malate (M) &amp; glutamate (G), adenosine diphosphate (ADP), succinate (S), oligomycin, and ascorbate (Asc) &amp; N,N,N,N-tetramethyl-phenylenediamine (TMPD). Complex I state 2 (CI-S2) was assessed as M+G, complex I state 3 (CI-S3) was assessed as (M+G+ADP)-(M+G), complex II state 3 (CII-S3) was assessed as (M+G+ADP+S)-(M+G+ADP), complex I&amp;II state 3 (CI&amp;II S3) was assessed as (M+G+ADP+S)-(M+G), state 4 (S4) was assessed after oligomycin, and complex IV (CIV) respiration was assessed after Asc+TMPD. The respiratory control ratio (RCR) was calculated as CI&amp;II-S3/S4. Results: Vasodilation in response to flow was reduced in ISC vs. CON (Δ-13.1±13.7%, p=0.01). but not in response to ACh (Δ-6.2±17.7%, p=0.23) or SNP (Δ1.7±11.0%, p=0.53). Additionally, CI-S2 (Δ-0.3±3.7 pmolO2·s−1·mg−1, p=0.65), S4 (Δ-1.7±4.4 pmolO2·s−1·mg−1, p=0.14), and CIV (Δ-2.8±20.9 pmolO2·s−1·mg−1, p=0.65) were not different between ISC and CON. However, CI-S3 (Δ-4.7±5.0 pmolO2·s−1·mg−1, p&lt;0.01), CII-S3 (Δ-3.5±5.0 pmolO2·s−1·mg−1, p=0.02), CI&amp;II-S3 (Δ-8.5±8.7 pmolO2·s−1·mg−1, p&lt;0.01), and RCR (Δ-0.8±1.3 pmolO2·s−1·mg−1, p=0.04) were all reduced in ISC vs. CON. Conclusions: We found that skeletal muscle microvessels and mitochondria were impaired in our swine model. Based on the present findings, we conclude that our novel porcine model closely replicates the pathophysiology PAD, making it a promising large animal model for studying human PAD. This research was supported by the National Institutes of Health (R01HD106911, R01AG062198, R01AG0778031) and the Great Plains IdeA-CTR (U54 GM115458). 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.

Abstract 1086: Singing Improves Vascular Function

Introduction: Singing is a physical activity with less reliance on skeletal muscle and more dependence on the diaphragm and cardiorespiratory systems. Unlike traditional exercise, the impact of singing on vascular health has not been studied. We hypothesized that older patients with known coronary artery disease (CAD) would have a favorable improvement in vascular endothelial function after 30 minutes of singing. Methods: Adult subjects with known CAD were recruited from cardiology clinics to participate in two singing sessions 30 minutes each and one control (rest period) session 2 to 7 days apart, according to a randomized, controlled, single-blind, crossover design. The two singing intervention sessions were (1) a pre-recorded video with a voice professor directing a ‘patient’ singing and (2) live singing coaching with a music therapist. Microvascular function was measured with peripheral arterial tonometry (PAT) before and after singing and expressed as Framingham reactive hyperemia index (fRHI). Macrovascular function was measured with brachial artery flow-mediated dilation. Cross-over treatment estimates of video, coaching, and control sessions were obtained with unbalanced ANOVA including the following variables: subject, the order of their visit, treatment, and its carry-over. Results: Sixty-five subjects (40% women, mean age 68±7) with CAD completed the study. Comorbidities included type 2 diabetes (29%), hypertension (75%), hyperlipidemia (85%), heart failure (19%), and self-reported physical or orthopedic limitations (54%). Compared to the control visit, there was a 26.5% (SE11.1%, p=0.0192) increase in fRHI in the video visit and a 17.3% (SE 10.7%, p=0.1081) increase in fRHI in the coaching visit. There was a small carryover effect with the video visit. There was no change in macrovascular endothelial function across the three different visits. Conclusions: Thirty minutes of singing improved microvascular endothelial function but not macrovascular endothelial function, in older patients with known CAD. This represents a potential biologic mechanism by which singing can benefit the cardiovascular system. Future studies should explore the sustained vascular adaptation to singing over weeks to months of singing.

Repeated daily exposure to mild intermittent hypoxia leads to a 8 week reduction in blood pressure and improvement in microvascular function in OSA patients with hypertension

Objective: We previously showed that blood pressure is reduced in individuals with obstructive sleep apnea (OSA) after 3 weeks of repeated daily exposure to mild intermittent hypoxia (MIH). However, we did not determine if these reductions are sustained over time. Likewise, the underlying mediator of these improvements is yet to be elucidated. Enhancement of microvascular function could lead to improved vasodilation and increased oxygen delivery to end organs and muscle. Furthermore, improvements in oxygen utilization could be indicative of heightened mitochondrial function. Therefore, in the present investigation we aimed to determine if reductions in blood pressure following treatment with MIH are sustained up to 8 weeks. We also explored if these changes were accompanied by modifications in microvascular function and oxygen utilization. Methods: Nineteen participants with OSA and hypertension have been enrolled in the study to date. Nine participants (8M, 1F) were randomized to a group treated with MIH while 10 participants were randomized to a group treated with sham MIH (8M, 2F). 5 participants in each group were also randomly assigned to use nightly continuous positive airway pressure (CPAP) for the duration of the study. Participants randomized to the MIH protocol were exposed to 12 — 2 minute episodes of 8% oxygen (PETO2 maintained at 50 mmHg) interspersed with room air. Following a ten-minute normoxic baseline, PETCO2 was maintained approximately 2 mmHg above baseline for the remainder of the protocol. Participants were exposed to this protocol for 15 days over a 3 week time period. Twenty-four hour blood pressure was measured using a Holter monitor programmed to measure blood pressure every 20 minutes starting at 6 AM. Microvascular function was assessed using a near infrared spectroscopy (NIRS) optode worn on the lateral gastrocnemius during a vascular occlusion test. These physiological measurements were obtained before and after 15 days of treatment, as well as, 4 and 8 weeks following treatment. Results: Age (45.22 ± 8.66 vs. 47.10 ± 9.48 years), BMI (31.59 ± 5.49 vs. 34.79 ± 4.57 kg/m2) and mean arterial pressure (105.00 ± 6.32 vs. 102.39 ± 6.52 mmHg) were similar at baseline prior to the start of the study. Similar to our previous findings, systolic (146.63 ± 8.00 mmHg vs. 132.67 ± 6.44 mmHg; p &lt; 0.01) and diastolic (86.79 ± 6.83 mmHg vs. 80.98 ± 5.64 mmHg; p &lt; 0.05) blood pressure was reduced immediately following treatment with MIH. This reduction was sustained for 4 and 8 weeks after treatment (p &lt; 0.01 and p &lt; 0.05 for all systolic and diastolic measurements respectively compared to baseline). This was not the case in the group treated with sham MIH. The maximal hyperemic response of oxygenated hemoglobin (HbO2) was significantly greater after treatment with MIH (127.06 ± 38.85% vs. 153.69 ± 31.51%; p &lt; 0.01). Likewise, a reduction in blood pressure from pre-MIH to post-MIH was correlated with a reduction in time to maximal response of HbO2 standardized to hyperemic amplitude (p &lt; 0.01; R2 = 0.754). Conclusions: Our results confirm that exposure to daily repeated MIH reduces blood pressure. In addition, we have shown that this reduction is sustained for up to 8 weeks. Likewise, our results suggest that improvements in microvascular function might contribute to the reduction in blood pressure along with improvement of mitochondrial utilization of oxygen. I01CX000125, IK6CX002287, R01HL142757, R56HL142757. 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.

Effect of home-based heat therapy on 24-h blood pressure and cutaneous microvascular function in post-menopausal women with hypertension

Hypertension is a leading risk factor for cardiovascular morbidity and mortality and is often accompanied by microvascular dysfunction. Despite a clear effcacy in men, standard antihypertensive medications are less effective in post-menopausal women. Consequently, adjuvant therapies are needed to improve blood pressure control and microvascular function in post-menopausal women. Heat therapy may fill this therapeutic gap as it has been shown to reduce blood pressure and improve microvascular function in healthy and certain clinical populations. Therefore, the purpose of this study was to test the hypothesis that 8 weeks of home-based heat therapy would improve 24-h blood pressure and cutaneous nitric oxide-dependent vasodilation in post-menopausal women with hypertension. Post-menopausal women (69 ± 5 y) with hypertension were randomized to 8 weeks of sham ( N = 15) or heat therapy ( N = 13). Participants immersed their lower legs ~33 cm into a circulated and temperature-controlled (sham: 35 °C; heat therapy: 42 °C) water bath 4 days per week, and 45 min per session. Blood pressure and cutaneous microvascular function and were assessed before (pre) and after (post) the 8-week intervention. Mean arterial blood pressure was measured across 24-h using an ambulatory monitor. To assess microvascular function, an intradermal microdialysis probe was inserted in the anterior aspect of the lower leg at a site directly exposed to water (immersed) and at another site not directly exposed (non-immersed). Red blood cell flux was measured (laser doppler flowmetry) during cutaneous hyperemia induced by 39 °C local heating. N(G)-nitro-L-arginine methyl ester (L-NAME; 20mM) was then infused in each probe until a nadir in red blood cell flux was achieved. Cutaneous vascular conductance was calculated as red blood cell flux divided by mean arterial pressure and normalized to maximal vasodilation (42 °C heating + 56 mM sodium nitroprusside; CVC%max). Nitric oxide-dependent dilation was calculated as the difference between CVC%max measured during the 39 °C plateau and the L-NAME nadir. Mean arterial blood pressure did not differ across time or between groups (sham: pre, 96 ± 5 mmHg vs. post, 96 ± 6 mmHg; heat therapy: pre, 97 ± 4 mmHg vs. 99 ± 7 mmHg; P = 0.5 for interaction). Cutaneous vasodilation induced by local heating did not differ across time for either group (sham: pre, 60 ± 19 CVC%max vs. post, 64 ± 12 CVC%max; heat therapy: pre, 68 ± 15 CVC%max vs. post, 63 ± 13 CVC%max) or between immersed and non-immersed sites ( P = 0.9 for interaction). Similarly, nitric oxide-dependent vasodilation did not differ across time or between sites for either group ( P = 1.0 for interaction). Taken together, 8 weeks of home-based heat therapy does not improve blood pressure or cutaneous microvascular function in post-menopausal women with hypertension. This work was supported by grants from the National Institutes of Health (T32 AG020494; R01AG059314; F32HL167556) and the American Heart Association (TPA958179). 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.

Repeated Exposure to Mild Intermittent Hypoxia Improves Walking Endurance in OSA Patients for 4 - 8 Weeks Post Therapy

Background: Approximately one billion adults globally are diagnosed with obstructive sleep apnea (OSA). Co-morbidities associated with sleep apnea include hypertension and increased susceptibility to fatigue linked to lower oxygen bioavailability and reduced exercise performance. Previously, we reported that daily exposure to mild intermittent hypoxia (MIH) reduces blood pressure following 3 weeks of treatment. These reductions in pressure could be coupled with improvements in microvascular function, fatigability and exercise performance. Objective: Thus, in the present investigation we explored if daily exposure to MIH improves walking endurance that is sustained for 8 weeks following treatment in individuals with OSA and hypertension (HTN). We also examined if improvements in endurance were correlated to modifications in microvascular function measured using near-infrared spectroscopy. Methods: To achieve this objective, both males and females with severe OSA and hypertension were randomly assigned to receive an MIH intervention (n=9) or Sham MIH (n=10). Half of the individuals in each group were also randomly assigned to nightly CPAP use. Based on the small sample size and the similarity of responses, the groups treated with MIH or sham MIH were combined independent of CPAP use. The MIH protocol consisted of twelve 2-minute hypoxic episodes (PETO2 ~ 50 mmHg), interchanged with 2 minutes of normoxia administered each day for 15 days. PETCO2 was sustained 2 mmHg above baseline throughout the protocol. To evaluate the impact of MIH on microvascular function, oxygen carrying capacity and fatigability, 10 minute walk tests (10 MWT) and vascular occlusion tests coupled with near infrared spectroscopy (NIRS) were performed before therapy, as well as, 5 days, 4 weeks, and 8 weeks after therapy. Results: No significant difference in distance, speed, and performance fatigue was found between the two groups during the 10 MWT before therapy. However, following therapy, the MIH group was able to walk further (p = 0.005), faster (p = 0.005), and were less fatigued (p = 0.009). These improvements were maintained for up to 8 weeks following treatment with MIH but not sham MIH. As anticipated, the total distance travelled was correlated to the performance fatigue index (r = -0.734, p &lt; 0.0001). The Δ in performance fatigue index was correlated to the Δ in the maximal hyperemic response of oxygenated hemoglobin (HbO2) (r = -0.461, p = 0.021) following treatment with MIH. Likewise, the perceived fatigability index was correlated to the Δ in the amplitude of the hyperemic HbO2 response (relative to measures obtained at the end of occlusion) (r = -0.397, p = 0.0494) and the Δ in the time to achieve the maximum HbO2 hyperemic response (r = 0.412, p = 0.041) following treatment with MIH. Conclusion: Our results show that distance, speed and performance fatigue are improved following treatment with MIH and that these improvements are sustained for 8 weeks. Our results also showed that correlations between improved performance, perceived fatigue and microvascular function were evident, providing the impetus to further investigate these relationships. Overall, our findings suggest that MIH may improve muscle endurance, allowing individuals with OSA and HTN to walk faster, longer, and with less fatigue for up to 8 weeks following 15 days of treatment with MIH. I01CX000125, IK6CX002287, R01HL142757, R56HL142757. 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.

Peripheral Endothelial and Microvascular Function with Repeated Far-infrared Sauna in Adults with Obesity

Obesity can lead to vascular dysfunction and elevated cardiovascular risk. Repeated far-infrared sauna bathing has improved cardiovascular function in cardiac patients. It is unknown if repeated far-infrared sauna bathing improves vascular function in adults with obesity. Purpose: We hypothesized that brachial artery flow-mediated dilation (FMD) and post-occlusion reactive hyperemia would be improved after 30 far-infrared sauna sessions in adults with obesity. Methods: Five adults with obesity (4 men, 1 woman; age: 33 ± 11; BMI: 36.3 ± 4.2 kg/m2) were assigned to a heat therapy (n=3) or time-control group (n=2). The heat therapy group completed 30 sessions of far-infrared sauna bathing (43 ± 4 min at 54 ± 2°C) at 3-4 times/week for 9 weeks. Peripheral vascular function was assessed before (PRE) and after (POST) the intervention. Brachial artery diameter and blood velocity were recorded via Doppler ultrasound for 1 min of baseline, 5 min of forearm occlusion, and 3 min of post-occlusion. FMD was calculated as the percent change from baseline diameter to peak diameter during post-occlusion. Relevant shear rate was calculated as the area under the curve (AUC) to peak dilation. Peak post-occlusion reactive hyperemia was defined as the peak blood flow during post-occlusion. Total post-occlusion reactive hyperemia was calculated as the AUC for blood flow above baseline for 3 min. Results: Baseline diameter did not differ at PRE vs. POST or between Control (3.76 ± 0.08 vs. 3.78 ± 0.09 mm) and Heat (4.25 ± 0.03 vs. 4.25 ± 0.02 mm) (all p &gt; 0.3977). FMD did not differ at PRE vs. POST and between Control (11.2 ± 5.2 vs. 10.6 ± 10.2%) or Heat (2.8 ± 2.4 vs. 6.2 ± 4.2%) (all p &gt; 0.2684). Relevant shear rate AUC did not differ at PRE vs. POST or between Control (27,412 ± 7,506 vs. 31,251 ± 20,608 a.u.) and Heat (16,538 ± 11,617 vs. 24,952 ± 10,639 a.u.) (all p &gt; 0.2577). Peak post-occlusion reactive hyperemia did not differ at PRE vs. POST or between Control (396 ± 42 vs. 387 ± 17 ml/min) and Heat (464 ± 40 vs. 441 ± 32 ml/min) (all p &gt; 0.1049). Total post-occlusion reactive hyperemia AUC was lower in Heat (140 ± 7 ml) vs Control (262 ± 12 ml) at PRE but did not differ across time or between groups at POST for Heat (212 ± 35 ml) vs Control (246 ± 66 ml). Conclusions: These preliminary data suggest there is no effect of 30 sessions of far-infrared sauna bathing on peripheral endothelial and microvascular function in adults with obesity. This may be due to the duration, frequency, and intensity of the far-infrared sauna compared to other passive heating modalities that have generated beneficial vascular adaptations in other studies. AHA 19TPA34890033. 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.