Venous Occlusion Plethysmography Research Articles

Aerobic exercise training combined with local strength exercise restores muscle blood flow and maximal aerobic capacity in long-term Hodgkin lymphoma survivors.

It is unclear whether muscle blood flow (MBF) is altered in long-term Hodgkin lymphoma (HL) survivors. We tested the hypothesis that 1) MBF response during mental stress (MS) is impaired in long-term HL survivors and 2) aerobic exercise training combined with local strength exercise (ET) restores MBF responses during MS in these survivors. Eighteen 5-year HL survivors and 10 aged-paired healthy subjects (HC) were studied. Twenty HL survivors were randomly divided into two groups: exercise-trained (HLT, n = 10) and untrained (HLUT, n = 10). Maximal aerobic capacity was evaluated by a cardiopulmonary exercise test and forearm blood flow (FBF) by venous occlusion plethysmography. MS was elicited by Stroop color and word test. ET was conducted for 4 mo, 3/wk for 60 min each session. The aerobic exercise intensity corresponded to anaerobic threshold up to 10% below the respiratory compensation point. The strength exercises consisted of two to three sets of chest press, pulley and squat exercises, 12-15 repetitions each exercise at 30-50% of the maximal voluntary contraction. Baseline was similar in HL survivors and HC, except peak oxygen consumption (peak V̇o2, P = 0.013) and FBF (P = 0.006) that were lower in the HL survivors. FBF responses during MS were lower in HL survivors (P < 0.001). ET increased peak V̇o2 (11.59 ± 3.07%, P = 0.002) and FBF at rest (33.74 ± 5.13%, P < 0.001) and during MS (24 ± 5.31%, P = 0.001). Further analysis showed correlation between the changes in peak V̇o2 and the changes in FBF during MS (r = 0.711, P = 0.001). In conclusion, long-term HL survivors have impaired MBF responses during MS. ET restores MBF responses during MS.NEW & NOTEWORTHY Long-term Hodgkin lymphoma (HL) survivors have impaired muscle blood flow responses during mental stress and decreased maximal aerobic capacity. Supervised aerobic exercise training combined with local strength exercises restores muscle blood flow responses during mental stress and maximal aerobic capacity in these survivors. These findings provide evidence of safety and effectiveness of exercise training in HL survivors. Moreover, they highlight the importance of exercise training in the treatment of this set of patients.

Augmented pressor responses to mental stress in females with spontaneous coronary artery dissection

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (&gt;80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. 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 Sex on the β-Adrenergic Receptor Contribution to Hypoxic Vasodilation

Introduction: Hypoxia elicits peripheral vasodilation to preserve oxygen delivery to tissues. Approximately 10% of hypoxic vasodilation has been attributed to β-adrenergic receptors on the vascular endothelium and smooth muscle. Based on data supporting greater vascular β-adrenergic receptor responsiveness in females compared to males, we examined the effect of sex on the relative contribution of the β-adrenergic receptors to hypoxic vasodilation. We hypothesized β-adrenergic receptor blockade (oral propranolol, 1 mg/kg) would attenuate hypoxic vasodilation and the effect would be greater in females compared to males. Methods: Five female (26±8 yrs, 22±2 kg/m2) and eight male (27±7 yrs, 26±2 kg/m2) participants completed two randomized, single-blinded, and placebo-controlled visits (NCT05256069). On each visit (placebo, propranolol), forearm blood flow (venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were measured during normoxia (SpO2 ~98%) and hypoxia (SpO2 ~80%). Blood flow was normalized for mean BP and expressed as forearm vascular conductance (FVC). The relative change in FVC with hypoxia (%FVC = Hypoxia − Normoxia / Normoxia x 100) was assessed as an index of hypoxic vasodilation. Differences in %FVC between study visits (propranolol − placebo) are reported. Results: %FVC was unaffected by β-adrenergic blockade in female (placebo 15±14%, propranolol -1±15%, p=0.066) and male (placebo 19±25%, propranolol 16±15%, p=0.755) participants. Any effect of β-adrenergic receptor blockade on hypoxic vasodilation did not differ by sex (females: -16±14%, males -3±29%; p=0.383). Conclusion: These preliminary data suggest any effect of β-adrenergic receptor blockade on hypoxic vasodilation does not differ between young healthy female and male participants, although studies are ongoing. Our results further understanding of the effect of sex on vascular control mechanisms during hypoxia. Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL). 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.

Near-Infrared Spectroscopy Does Not Track Forearm Blood Flow during Venous Occlusion Plethysmography

Background: Venous occlusion plethysmography (VOP) non-invasively measures forearm blood flow (FBF), whereas near-infrared spectroscopy (NIRS) assesses skeletal muscle oxygenation. Using these techniques has revealed sex differences in microvascular responses. However, it is not clear if NIRS and VOP results are interchangeable under various conditions like reactive hyperemia (RH). Our purpose was to evaluate sex-specific associations between FBF and NIRS-derived parameters: oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin, and hemoglobin difference (O2Hb, HHb, tHb, and HbDiff). Methods: In total, 29 adults (15 men) participated, and a strain-gauge was placed on the forearm for VOP and a NIRS device was distally attached. Slopes for FBF and NIRS parameters were quantified during venous occlusion intervals at rest and during RH. Pearson’s correlations were assessed between VOP and NIRS slopes. Intraclass correlation coefficients (ICC2,1) examined the sex-specific consistency of the slopes at rest. p ≤ 0.05 was considered significant. Results: During RH, FBF was not correlated with O2Hb (r = −0.126), HHb (r = 0.228), tHb (r = 0.061), or HbDiff (r = 0.046). Seemingly, there were no sex differences. Resting FBF and NIRS-derived variables, except for HbDiff, displayed suitable consistency as suggested by the reliability results (ICC2,1 = 0.115–0.577). Conclusions: The NIRS values collected did not match the strain-gauge slopes. Individuals should practice caution when generating blood flow inferences from NIRS-based data during VOP.

Association between peripheral and respiratory muscle strength and gait speed in the elderly is not mediated by peripheral muscle blood flow

BackgroundThe aging process affects different systems, including the musculoskeletal and respiratory systems. Both systems seem to be interconnected in relation to functional capacity deterioration in the elderly. Therefore, this study aimed to evaluate the association between peripheral and respiratory muscle strength with gait speed and its possible mediation by leg muscle blood flow (LBF) in the elderly. MethodsPeople aged over 65 years, of both sexes and clinically stable were evaluated. Gait speed was evaluated by the 4.6 m walking test. Maximal inspiratory pressure (MIP) and expiratory pressure (MEP) by manuvacuometry, Handgrip strength by a dynamometer (Jamar®) and LBF by venous occlusion plethysmography. ResultsWe included 110 patients with mean age 76.9 ± 7.2 years, 56 (50.9 %) were women, 72 (67.9 %) were classified as frail by Fried criteria and 22 (20.0 %) reported the regular practice of exercise. Baseline mean values of MIP was 59.5 ± 23.8 and MEP 68.2 ± 23.8. The median gait speed was 0.88 m/s, handgrip strength 19.5 Kg/f and LBF 2.7 ml/min/100 ml. Further analysis showed a significant association between gait speed and handgrip strength with MIP (p = 0.005, p = 0.013, respectively). However, no mediation by LBF were found. ConclusionThere is a strong association between gait speed and handgrip strength with MIP without mediation by LBF.

Sleep-induced limb vasodilation in individuals confined to bed for 24 h

The sleep/wake rhythm in limbs has been scarcely studied, especially due to the difficulty associated with continuous monitoring of arterial flow to the forearm and leg for a 24-h period. Addressing this constraint, we employed indium-gallium-in-silicone strain-gauge venous-occlusion plethysmography, an automated method facilitating the measurement of 24-h limb arterial flow in bed-confined subjects without disturbing their natural sleep. This article presents the state of the art in this field. Our examination of 60 healthy normotensive individuals revealed a distinctive sleep/wake rhythm in limb arterial flow, characterized by elevated values during sleep (32.7% in the forearm, P &lt; 0.0001; 39.1% in the leg, P &lt; 0.0001). Correspondingly, limb resistance mirrored the trend of flow (-32.7%, P &lt; 0.0001; -33.5%, P &lt; 0.0001), with these variations attributed to sleep-induced limb vasodilation. Sleep-associated vasodilation was also evident in 21 hypertensive individuals (leg resistance: -33.1%, P &lt; 0.0001) and 13 heart transplant recipients lacking vagal and sympathetic cardiac innervation (resistance: -33.6%, P &lt; 0.0001). On the contrary, among 11 subjects with an interrupted spinal cord, we observed forearm vasodilation (resistance: -36.6%, P &lt; 0.0001) but observed no leg vasodilation if the spinal lesion was under T2 (innervating the leg). Furthermore, a loss of sleep-induced vasodilation occurred in both the forearm and leg if the injury was above C7 (innervating both forearm and leg). Our conclusion posits the existence of sleep-induced limb vasodilation, a phenomenon attributed to signals traveling along the spinal cord, with the heart playing no discernible role in this rhythmic process, and arterial hypertension deemed irrelevant. Comprehensive further studies are imperative to elucidate the precise triggers of limb vasodilation during sleep.

Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist.

Buloxibutid (also known as C21) is a potent and selective angiotensin II type 2 receptor (AT2R) agonist, in development for oral treatment of fibrotic lung disease. This phase I, open-label, pharmacodynamic study investigated vascular effects of buloxibutid in five healthy male volunteers. Subjects were administered intra-arterial infusions of buloxibutid for 5 min in ascending doses of 3, 10, 30, 100, and 200 μg/min, infused sequentially in the forearm. Infusions of sodium nitroprusside (SNP) solution in doses of 0.8-3.2 μg/min were administered as a positive control. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Safety and tolerability of intra-arterial administrations of buloxibutid were evaluated. Following infusion of buloxibutid in doses of 3-200 μg/min, the range of increase in FBF was 27.8%, 17.2%, 37.0%, 28.5%, and 60.5%, compared to the respective baseline. The largest increase was observed in the highest dose group. Infusions of SNP as a positive control, increased FBF 230-320% compared to baseline. Three adverse events (AEs) of mild intensity, not related to buloxibutid or SNP, were reported for two subjects. Two of these AEs were related to study procedures. There were no clinically relevant changes in arterial blood pressure during the study period. Intra-arterial infusion of buloxibutid in low, ascending doses increased FBF, indicating that buloxibutid may be effective in conditions associated with endothelial dysfunction. Venous occlusion plethysmography was found to be a useful method to explore pharmacodynamic vascular effects of novel AT2R agonists, while avoiding systemic adverse effects.

Endothelial Dysfunction and Heart Failure with Preserved Ejection Fraction-An Updated Review of the Literature.

Heart failure (HF) is a clinical syndrome consisting of typical symptoms and signs due to structural and/or functional abnormalities of the heart, resulting in elevated intracardiac pressures and/or inadequate cardiac output. The vascular system plays a crucial role in the development and progression of HF regardless of ejection fraction, with endothelial dysfunction (ED) as one of the principal features of HF. The main ED manifestations (i.e., impaired endothelium-dependent vasodilation, increased oxidative stress, chronic inflammation, leukocyte adhesion, and endothelial cell senescence) affect the systemic and pulmonary haemodynamic and the renal and coronary circulation. The present review is aimed to discuss the contribution of ED to HF pathophysiology-in particular, HF with preserved ejection fraction-ED role in HF patients, and the possible effects of pharmacological and non-pharmacological approaches. For this purpose, relevant data from a literature search (PubMed, Scopus, EMBASE, and Medline) were reviewed. As a result, ED, assessed via venous occlusion plethysmography or flow-mediated dilation, was shown to be independently associated with poor outcomes in HF patients (e.g., mortality, cardiovascular events, and hospitalization due to worsening HF). In addition, SGLT2 inhibitors, endothelin antagonists, endothelial nitric oxide synthase cofactors, antioxidants, and exercise training were shown to positively modulate ED in HF. Despite the need for future research to better clarify the role of the vascular endothelium in HF, ED represents an interesting and promising potential therapeutic target.

Sympathetic Neural Overdrive and Diminished Exercise Capacity in Reduced Ejection Fraction Heart Failure Related to Anthracycline- Based Chemotherapy.

Cardiotoxicity is the most worrying cardiovascular alteration in patients treated with chemotherapy. To improve the understanding regarding the cardiotoxicity, we studied whether: 1) patients with cardiac dysfunction related to anthracycline-based chemotherapy have augmented sympathetic nerve activity and decreased exercise capacity and 2) these responses are similar to those observed in patients with heart failure caused by other etiologies. Sixteen patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy with or without chest radiation (HFrEFCA), 10 patients with heart failure with reduced ejection not related to cancer therapy (HFrEF), and 16 age-and body mass index (BMI)-matched healthy controls were studied. Left ventricular ejection fraction (LFEF, Echocardiography), peak oxygen consumption (peak V̇O2, cardiopulmonary exercise test), muscle sympathetic nerve activity (MSNA, microneurography) and forearm blood flow (FBF, venous occlusion plethysmography) were measured. We found that peak oxygen consumption peak V̇O2 and LVEF were significantly reduced in patients with HFrEFCA compared to controls (P<0.0001) but similar to those found in HFrEFCA patients. The sympathetic nerve activity burst frequency and incidence were significantly higher in patients with HFrEFCA than in controls (P<0.0001). No differences were found between HFrEF and HFrEFCA patients. Peak V̇O2 was inversely associated with MSNA burst frequency (r=-0.53, P=0.002) and burst incidence (r=-0.38, P=0.01), and directly associated with LVEF (r=0.71, P<0.0001). Taken together, we conclude that patients who develop heart failure due to anthracycline-based chemotherapy have sympathetic neural overdrive and reduced exercise capacity. In addition, these physiological changes are similar to those observed in patients with HFrEF.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

#6650 SGLT2-INHIBITION IMPROVES VASCULAR FUNCTION IN TYPE 2 DIABETES: A DOUBLE BLIND, RANDOMIZED, PLACEBO CONTROLLED CROSSOVER TRIAL

Abstract Background and Aims Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and protects kidney function in type 2 diabetes (DM2) patients. These benefits may partly be related to improvement of vascular function. In this study we examined the effects of SGLT2i treatment on vasodilatory capacity in patients with DM2. Method Using a double-blind, randomized, placebo-controlled cross-over study design, we included 15 patients with DM2 and preserved kidney function (eGFR &amp;gt; 60 ml/min/1.73 m2). Each participant received four weeks of SGLT2i treatment (empagliflozin 10 mg once daily) or matching placebo. After a two-week wash-out period, each participant was crossed over to four weeks of the opposite treatment. At the end of each treatment period, vascular function was evaluated by venous occlusion plethysmography. Forearm blood flow (FBF) was measured during intra-arterial infusion of increasing concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP), assessing endothelium-dependent and independent vasodilation, respectively. Repeated measures two-way ANOVA was performed to compare absolute FBF between groups. Results 11/15 (73%) of participants were male. Mean age was 68±9 (SD) years (range 49-82), eGFR was 81±10 ml/min/1.73 m2 and duration of diabetes was 15.8±9 years. 11/15 (73%) had hypertension and 9/15 (60%) received treatment with an ACE-inhibitor or Angiotensin-II blocker. 4/15 (27%) had cardiovascular disease. The median albumin-to-creatinine ratio was 29 mg/g (range: 4-1293). Both ACh and SNP dose-dependently increased FBF (Figure 1 and 2). FBF during SNP infusion was significantly higher during empagliflozin treatment as compared to placebo (p = 0.004), whereas there was no difference between empagliflozin and placebo in FBF during ACh infusion (P = 0.399). Conclusion Empagliflozin improves endothelium-independent vasodilatation in patients with DM2, whereas no changes could be observed in endothelium-dependent vasodilation. These results suggest that SGLT2i positively affects vascular function and that the effect is not related to nitric oxide from the endothelium.

#4063 APELIN INCREASES FOREARM BLOOD FLOW IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) affects 1 in 10 people and cardiovascular disease is its commonest complication. Despite current standard of care, many patients continue to progress to kidney failure and/or die of cardiovascular disease. Thus, there is an urgent unmet need for new treatments that slow kidney function decline and offer broad cardiovascular protection. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is an attractive therapeutic target for CKD. Apelin is an endothelium-dependent vasodilator and a potent inotrope. Clinical studies show that apelin improves endothelial function in health and heart failure, and pre-clinical studies in models of kidney disease find apelin offers renoprotection. At present, apelin has not been studied in patients with CKD. The aims of this study were to examine the local vascular actions of apelin in CKD. Method Participants with stable, non-diabetic CKD and age- and sex-matched healthy volunteers were recruited to a prospective, randomised, placebo-controlled study. Blood pressure and arterial stiffness (measured using pulse wave velocity) were assessed at baseline. Endothelial function was examined using gold-standard venous occlusion plethysmography. Forearm vasodilatation was measured in response to incremental intra-arterial doses of acetylcholine (7.5, 15 and 30 μg/min, used to assess endothelium-dependent vasodilatation), sodium nitroprusside (1, 2 and 4 μg/min, used to assess endothelium-independent vasodilatation), and pyroglutamated apelin-13 ([Pyr1]apelin-13; 0.3, 1, 3, 10, 30 and 100 nmol/min). Circulating tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were assessed as measures of endogenous fibrinolysis. Results Fifteen patients with CKD (mean age 55±4 years; 53% male) and 15 healthy volunteers (mean age 51±3 years; 67% male) completed the study. In comparison to healthy volunteers, patients with CKD had a higher blood pressure (mean arterial pressure: 102 mmHg versus 93 mmHg, p&amp;lt;0.05) and increased pulse wave velocity (7.5±2.2 m/s versus 6.0±0.9 m/s, p&amp;lt;0.01). Similar dose-dependent vasodilatation to acetylcholine and sodium nitroprusside was seen in both groups. [Pyr1]apelin-13 increased forearm blood flow by a maximum of ∼30% in both health and CKD (p&amp;lt;0.01 compared to baseline for both) (Figure 1). This response appeared to be dose-dependent. Net tPA antigen release increased 20-70 fold in response to [Pyr1]apelin-13 in both health and CKD, with a trend to a greater release in CKD. There was no change in PAI-1. No relationship was seen between the response to [Pyr1]apelin-13 and kidney function. Conclusion Apelin promotes vasodilatation in optimally managed patients with CKD and may regulate endogenous fibrinolysis. If this effect were maintained in the long-term with systemic apelin treatment, it would be expected to reduce cardiovascular risk. Systemic studies are now justified to investigate the haemodynamic and renal effects of apelin in these patients.

The effect of vitamin C on nitroglycerin-mediated vasodilation in individuals with and without the aldehyde dehydrogenase 2 polymorphism.

To mediate its pharmacodynamic effects, glyceryl trinitrate (GTN) requires bioactivation, by which it releases nitric oxide or a nitric oxide moiety. The exact mechanism of GTN bioactivation remains uncertain. Mitochondrial aldehyde dehydrogenase (ALDH-2) has been proposed as the primary enzyme responsible for this bioactivation process. Evidence for the importance of ALDH-2 in GTN bioactivation has been inconsistent, particularly in human models. An alternative hypothesis suggests that decreased ALDH-2 activity leads to accumulation of reactive cytotoxic aldehydes, which either inhibit the vasoactive product(s) of GTN or impair other enzymatic pathways involved in the bioactivation of GTN. We investigated the effect of supplemental vitamin C on vascular responses to GTN in healthy volunteers of East Asian descent, of whom 12 with and 12 without the ALDH-2 polymorphism participated. Subjects underwent 2 sequential brachial artery infusions of GTN at rates of 5, 11 and 22 nmol/min, separated by a 30-min washout period. The GTN infusions were carried out in the presence and absence of vitamin C using a randomized, crossover design. Venous occlusion plethysmography was used to measure forearm blood flow responses to GTN. Compared to subjects with functional ALDH-2, the variant group exhibited blunted hemodynamic responses to intra-arterial GTN infusions, although this reduction in response was not statically significant. Contrary to our hypothesis, vitamin C had an inhibitory effect on GTN mediated vasodilation as compared to GTN during saline in both groups. We conclude that vitamin C did not augment the acute vascular response to GTN in those with the ALDH-2 polymorphism.

Atazanavir-induced unconjugated hyperbilirubinemia prevents vascular hyporeactivity during experimental human endotoxemia.

Inflammation-induced free radical release is important in the pathogenesis of several diseases, including atherosclerosis and sepsis. Heme oxygenase (HO) breaks down heme into carbon monoxide, iron, and biliverdin. Biliverdin IXα is directly converted to bilirubin by biliverdin reductase. Unconjugated bilirubin is a powerful antioxidant, and elevated levels have beneficial effects in preclinical models and human cardiovascular disease. However, its impact during acute inflammation in humans is unknown. In the present study, we investigated the impact of atazanavir-induced (unconjugated) hyperbilirubinemia on antioxidant capacity, inflammation, and vascular dysfunction in human experimental endotoxemia. Following double-blinded four-day treatment with atazanavir 2dd300 mg (or placebo), twenty healthy male volunteers received 2 ng/kg Escherichia coli lipopolysaccharide intravenously. Blood was drawn to determine the bilirubin levels, antioxidant capacity, and cytokine response. It was demonstrated that following atazanavir treatment, total bilirubin concentrations increased to maximum values of 4.67 (95%CI 3.91-5.59) compared to 0.82 (95%CI 0.64-1.07) mg/dL in the control group (p<0.01). Furthermore, the anti-oxidant capacity, as measured by the ferric-reducing ability of plasma (FRAP), was significantly increased with 36% in hyperbilirubinemia subjects (p<0.0001), and FRAP concentrations correlated strongly to bilirubin concentrations (R2=0.77, p<0.001). Hyperbilirubinemia attenuated the release of interleukin-10 from 377 (95%CI 233-609) to 219 (95%CI 152-318) pg/mL (p=0.01), whereas the release of pro-inflammatory cytokines remained unaltered. In vitro, in the absence of hyperbilirubinemia, atazanavir did not influence lipopolysaccharide-induced cytokine release in a whole blood assay. Vascular function was assessed using forearm venous occlusion plethysmography after intra-arterial infusion of acetylcholine and nitroglycerin. Hyperbilirubinemia completely prevented the LPS-associated blunted vascular response to acetylcholine and nitroglycerin. Atazanavir-induced hyperbilirubinemia increases antioxidant capacity, attenuates interleukin-10 release, and prevents vascular hyporesponsiveness during human systemic inflammation elicited by experimental endotoxemia. http://clinicaltrials.gov, identifier NCT00916448.

Strain-gauge venous occlusion plethysmography: An objective and non-invasive approach to the evaluation of venous hemodynamics in patients with acute deep-vein thrombosis undergoing post-pharmacomechanical thrombolysis.

Strain-gauge venous occlusion plethysmography (SGVOP) is a means of acquiring hemodynamic data non-invasively, unlike other methods used routinely for the diagnosis and follow-up of venous diseases. The present study compares the plethysmographic data with early- and mid-term routine data of patients with acute deep-vein thrombosis (DVT) who underwent pharmacomechanical thrombolysis. Included in this retrospective study were 118 patients with acute DVT, who underwent pharmacomechanical thrombolysis between February 2018 and July 2019. Pre- and post-procedure follow-up data including CIVIQ-20 (quality of life), VCSS (Venous Clinical Severity Score), D-Dimer, Doppler USG results, venous capacity (VC), and venous outflow (VO) obtained by SGVOP were recorded and compared. In all 118 (100%) patients who underwent the procedure, early- and mid-term patency was seen to have been provided on Doppler USG follow-up, and various degrees of venous insufficiency were identified. A statistically significant improvement was observed in VCSS, CIVIQ-20, D-Dimer, VO, and VC measurements, although when the discrepancies between CIVIQ-20 and plethysmographic measurements were examined individually during the 6-month follow-up, nine (13.1%) patients were identified with comorbidities. Pharmacomechanical thrombolysis is an effective treatment approach for patients with acute DVT. Providing non-invasive objective data supporting the diagnosis and follow-up of venous diseases, the SGVOP approach offers significant benefits and should be considered more frequently as a viable therapy.

Enhanced protection with ischemic preconditioning against endothelial ischemia-reperfusion injury during the luteal phase of the menstrual cycle in premenopausal women

PURPOSE: In premenopausal women, we have previously shown that the capacity of remote ischemic preconditioning (IPC) to protect against endothelial ischemia/reperfusion (I/R) injury is diminished during the early follicular phase of the menstrual cycle compared with the late follicular phase. The aim of this research was to extend our initial findings by determining how the luteal phase of the menstrual cycle influences remote IPC to alleviate endothelial I/R injury in a second sample of women. It was hypothesized that the capacity of remote IPC to alleviate endothelial I/R injury will be greater during the luteal phase of the menstrual cycle compared with the early follicular phase. METHODS: Eleven premenopausal eumenorrheic women (age 24±3 yr.) not taking any contraceptive medications were studied. Primary outcomes were the assessment of vascular endothelial function measured during the early follicular (after onset of menses; days 1-6) and at the peak luteal phase (days 21-24 after positive urine progesterone test). Endothelium-dependent vasodilation was assessed by the forearm blood flow (FBF) response to reactive hyperemia using venous occlusion plethysmography with and without endothelial I/R injury (20 min brachial artery ischemia, 15 min reperfusion) when preceded by remote IPC (3×5 min cycles of arm ischemia). RESULTS: Without endothelial I/R injury, peak FBF was similar (P=0.25) between the early follicular (26.6±5.0 ml/100 ml tissue/min) and luteal phases (25.1±3.9 ml/100 ml tissue/min). In contrast, there was a significant main effect (P&lt;0.001) of cycle phase on the capacity of IPC to protect against endothelial I/R injury. During the early follicular phase, peak FBF was significantly (P&lt;0.001) diminished 18% with endothelial I/R injury (from: 26.6±5.0 to 21.8±4.6 ml/100 ml tissue/min) despite remote IPC. As a result, total FBF during reactive hyperemia (area under the curve) was decreased ~25% (P=0.006) after (45.1±10.0) compared with before (59.8±14.1 ml/100 ml tissue) endothelial I/R injury. However, during the luteal phase endothelial I/R injury was prevented with remote IPC. Indeed, in the presence of endothelial I/R injury, peak FBF was well preserved (from: 25.1±3.9 to 27.2±5.7 ml/100 ml tissue/min; P=0.267). As a result, total FBF was similar (P=0.774) after (55.9±13.3) compared with before (51.7±13.8 ml/100 ml tissue) endothelial I/R injury. The level of endothelial protection from I/R injury with remote IPC during the luteal phase was similar (P=0.34) to the late follicular phase in our previous study. CONCLUSIONS: IPC-mediated vascular endothelial protection is robust during the luteal phase of the menstrual cycle but wanes in the early follicular phase. Greater circulating estrogens and perhaps progesterone during the luteal phase may contribute to the protective benefits of IPC in women, and sheds light about how cardioprotection may change with ovarian hormone deficiency with the menopause transition. This is the full abstract presented at the American Physiology Summit 2023 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.

Nitric oxide contribution to endothelium-mediated vasodilation is attenuated in postmenopausal compared to premenopausal females

Background: Hypertension prevalence increases in females following menopause. Poor endothelial microvascular function increases risk of hypertension. Endothelial-mediated vasodilation is dependent on nitric oxide (NO). Estrogen enhances NO production; therefore, reduced estrogen levels in postmenopausal females may result in a reduced contribution of NO to endothelial-mediated vasodilation, although studies are limited. Herein, we aimed to investigate the contribution of NO to endothelial-mediated vasodilation in premenopausal and postmenopausal females. We hypothesized that postmenopausal females would have attenuated endothelium-mediated vasodilation and reduced contribution of NO compared to premenopausal females. Methods: Ten premenopausal (27±3 yrs) and eleven postmenopausal (59±4 yrs) normotensive females were studied. Resting brachial blood pressures were measured using a standard arm cuff. Brachial arterial catheters were placed for continuous blood pressure measurement and pharmacologic infusions. Forearm blood flow (FBF) was measured using venous occlusion plethysmography at baseline (saline) and during infusion of an endothelium-dependent vasodilator (acetylcholine; 1.0, 2.0, 4.0, and 8.0 μg/100mL tissue/min) with and without a NO synthase inhibitor (L-NG-monomethylarginine [L-NMMA]; 1.0 mg/min) co-infusion. Forearm vascular conductance (FVC) was calculated as FBF/mean arterial pressure✕100. Data were analyzed using a two-way repeated-measures ANOVA. Results: Resting systolic blood pressure (SBP) but not diastolic blood pressure (DBP) was greater in postmenopausal compared to premenopausal females (SBP: 121±15 vs. 103±9 mmHg, respectively; P&lt;0.01; DBP: 72±11 vs. 65±5 mmHg, respectively; P=0.07). FBF responses to acetylcholine did not differ between premenopausal and postmenopausal females (Group Main Effect: P=0.11). When correcting for blood pressure, premenopausal females exhibited greater FVC responses to acetylcholine compared to postmenopausal females (Group Main Effect: P=0.04). In premenopausal females, FBF and FVC responses to acetylcholine were reduced with co-infusion of L-NMMA compared to acetylcholine infusion only (L-NMMA Main Effect: P=0.02 and P=0.01, respectively). In postmenopausal females, the FBF and FVC responses to acetylcholine were unaffected by L-NMMA (L-NMMA Main Effect: P=0.79 and P=0.76, respectively). Conclusion: Compared to premenopausal females, postmenopausal females have impaired endothelial microvascular function. Attenuated NO contribution during endothelium-mediated vasodilation in postmenopausal women may partially contribute to the increased hypertension risk in this population. AHA 14PRE18040000, AHA 898649, NIH HL083947, NIH HL148144, NCATS UL1 TR000135 This is the full abstract presented at the American Physiology Summit 2023 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 obesity on the vascular response to sympathetic activation during hypoxia in female participants

Background: Activation of the sympathetic nervous system causes vasoconstriction and an acute reduction in peripheral blood flow. However, during hypoxia, sympathetically-mediated vasoconstriction is attenuated in young females without obesity. Given sustained increases in sympathetic activity associated with obesity may create a greater propensity to vasoconstrict in response to sympathetic activation, we sought to examine the effect of obesity on the vascular response to sympathetic activation during hypoxia. We hypothesized sympathetically-mediated vasoconstriction during hypoxia would be greater in premenopausal female adults with obesity when compared to females without obesity. Methods: Blood pressure (BP, finger photoplethysmography) and forearm blood flow (FBF, venous occlusion plethysmography) were assessed in premenopausal female adults with obesity (n=5, 25±3 yrs, 37±1 kg/m2, 48±1% body fat) and without obesity [n=19, 23±1 yrs, 23±1 kg/m2, (33±2% body fat, n=8)]. Data were combined from two cohorts (IRB #2022525, 2011312) to test present hypotheses. Participants completed two trials consisting of a 2-min cold pressor test (CPT) during baseline normoxia (98±1% SpO2) and following 3-5 min of steady-state hypoxia (0.10±0.01 FiO2, 82±1% SpO2). FBF was normalized for BP (forearm vascular conductance, FVC) and a change in FVC during the last 1-min of CPT was calculated (ΔFVC). The main effect of group (obese, non-obese), condition (normoxia, hypoxia) and the interaction of group and condition were compared using a two-way repeated measures ANOVA. Results: In female participants without obesity, ΔFVC during normoxia was attenuated during hypoxia (-0.57±0.19 vs +0.36±0.34 mL/dL/100mmHg/min; p=0.009). Conversely, in female participants with obesity, ΔFVC during normoxia did not differ from the response during hypoxia (-0.31±0.46 vs -0.87±0.34 mL/dL/100mmHg/min; p=0.382). Group differences in ΔFVC were not observed during normoxia (p=0.657), but were present during hypoxia (p=0.039). Conclusion: Sympathetically-mediated vasoconstriction is attenuated during steady-state hypoxia in premenopausal females without obesity, whereas this response is not observed in female adults with obesity. These preliminary data advance our understanding of the impact of obesity on hypoxic vascular control in premenopausal female participants and have implications for conditions in which hypoxia and sympathetic activation are observed ( e.g., sleep apnea, heart failure, COVID-19). NIH HL130339 (JKL), NIH HL153523 (JKL), AHA 909014 (DWJ) This is the full abstract presented at the American Physiology Summit 2023 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.

Microvascular Function, Inflammatory Status, and Oxidative Stress in Post-Bariatric Patients with Weight Regain

Weight loss after bariatric surgery in obesity improves vascular function and metabolic/inflammatory profiles and reduces cardiovascular mortality but there are limited data on the effects of weight regain on vascular health. We compared the metabolic/inflammatory profiles, oxidative status, and vascular function of post-bariatric patients with a high ratio of weight regain (RWR) vs. non-surgical controls. Thirty-two post-bariatric patients [Roux-en-Y gastric bypass; aged = 44 ± 8 years, BMI = 40.1 ± 7.7 kg/m2, and RWR = 58.7 ± 24.3%] and thirty controls that were BMI-, age-, and gender-matched entered the study. We collected clinical data, metabolic/inflammatory/oxidative stress circulating biomarkers, and endothelial/microvascular reactivity through Venous occlusion plethysmography and Laser speckle contrast imaging. The bariatric group exhibited lower neck circumference, fasting glucose, and triglycerides than the non-surgical group, while HDL-cholesterol was higher in the bariatric group (p &lt; 0.001). There was no significant difference between groups for endothelial/microvascular reactivities (p ≥ 0.06). Resistin, leptin, endothelin-1, soluble forms of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, tumor necrosis factor-α, and thiobarbituric acid reactive substances did not differ significantly between groups (p ≥ 0.09) either. The adiponectin level was higher in the bariatric compared to the non-surgical group, while interleukin-6 was lower in the bariatric group (p &lt; 0.001). Despite the fact that endothelial/microvascular functions were not significantly different between groups, post-bariatric patients present partially preserved metabolic/inflammatory benefits even with high RWR.

A Cross-Sectional Study of Adiposity by DXA and the Relationship with Endothelial Function and Low-Grade Inflammation

Introduction: To evaluate body composition, especially visceral adipose tissue (VAT), by dual-energy x-ray absorptiometry (DXA) and its relation to endothelial function investigated by venous occlusion plethysmography (VOP) and ultrasensitive C-reactive protein (hsCRP). Methodology: This is a cross sectional study in adults of both sexes divided into group 1 (BMI, 20-24.9, n=30), group 2 (BMI, 25-29.9, n=22), group 3 (BMI, 30-34.9, n=27) and group 4 (BMI, 35-39.9, n=22). VAT was analyzed, among other parameters of adiposity, by DXA Lunar iDXA, and co-related to endothelial function, anthropometric evaluation, cardiometabolic variables and hsCRP. For statistical analysis, tests of comparison between groups and correlation were performed using the software SPSS version 25. Results: Inverse correlation of TFT (total fat mass), % RFM (regional fat mass), FMI (fat mass index) and VAT were identified with increment of arterial blood flow in VOP, except the decrease of the latter, with increase of BMI, adiposity indexes, especially VAT, between groups. hsCRP values showed a direct correlation with progression of adiposity and VAT, between groups. Conclusions: VAT progression, by DXA analysis, was associated with a decline in endothelial function and increase of inflammation, demonstrating potential use in early identification of individuals with cardiovascular risk (CVR).