Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease, 2) determine whether female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity, and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Finally, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes.

Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that 1) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness, 2) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase, and 3) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Lastly, we demonstrated that in vivo treatment of db/db mice with adropin for 4 wk reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelium-derived NO, and thus support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.NEW & NOTEWORTHY Arterial stiffening, a characteristic feature of obesity and type 2 diabetes (T2D), contributes to the development and progression of cardiovascular diseases. Herein we establish that adropin is decreased in obese and T2D models and furthermore provide evidence that reduced adropin may directly contribute to arterial stiffening. Collectively, findings from this work support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.

Young Women Are Protected Against Vascular Insulin Resistance Induced by Adoption of an Obesogenic Lifestyle.

Vascular insulin resistance is a feature of obesity and type 2 diabetes that contributes to the genesis of vascular disease and glycemic dysregulation. Data from preclinical models indicate that vascular insulin resistance is an early event in the disease course, preceding the development of insulin resistance in metabolically active tissues. Whether this is translatable to humans requires further investigation. To this end, we examined if vascular insulin resistance develops when young healthy individuals (n = 18 men, n = 18 women) transition to an obesogenic lifestyle that would ultimately cause whole-body insulin resistance. Specifically, we hypothesized that short-term (10 days) exposure to reduced ambulatory activity (from >10 000 to <5000 steps/day) and increased consumption of sugar-sweetened beverages (6 cans/day) would be sufficient to prompt vascular insulin resistance. Furthermore, given that incidence of insulin resistance and cardiovascular disease is lower in premenopausal women than in men, we postulated that young females would be protected against vascular insulin resistance. Consistent with this hypothesis, we report that after reduced ambulation and increased ingestion of carbonated beverages high in sugar, young healthy men, but not women, exhibited a blunted leg blood flow response to insulin and suppressed skeletal muscle microvascular perfusion. These findings were associated with a decrease in plasma adropin and nitrite concentrations. This is the first evidence in humans that vascular insulin resistance can be provoked by short-term adverse lifestyle changes. It is also the first documentation of a sexual dimorphism in the development of vascular insulin resistance in association with changes in adropin levels.

Endothelial Glycocalyx.

The glycocalyx is a polysaccharide structure that protrudes from the body of a cell. It is primarily conformed of glycoproteins and proteoglycans, which provide communication, electrostatic charge, ionic buffering, permeability, and mechanosensation-mechanotransduction capabilities to cells. In blood vessels, the endothelial glycocalyx that projects into the vascular lumen separates the vascular wall from the circulating blood. Such a physical location allows a number of its components, including sialic acid, glypican-1, heparan sulfate, and hyaluronan, to participate in the mechanosensation-mechanotransduction of blood flow-dependent shear stress, which results in the synthesis of nitric oxide and flow-mediated vasodilation. The endothelial glycocalyx also participates in the regulation of vascular permeability and the modulation of inflammatory responses, including the processes of leukocyte rolling and extravasation. Its structural architecture and negative charge work to prevent macromolecules greater than approximately 70 kDa and cationic molecules from binding and flowing out of the vasculature. This also prevents the extravasation of pathogens such as bacteria and virus, as well as that of tumor cells. Due to its constant exposure to shear and circulating enzymes such as neuraminidase, heparanase, hyaluronidase, and matrix metalloproteinases, the endothelial glycocalyx is in a continuous process of degradation and renovation. A balance favoring degradation is associated with a variety of pathologies including atherosclerosis, hypertension, vascular aging, metastatic cancer, and diabetic vasculopathies. Consequently, ongoing research efforts are focused on deciphering the mechanisms that promote glycocalyx degradation or limit its syntheses, as well as on therapeutic approaches to improve glycocalyx integrity with the goal of reducing vascular disease. © 2022 American Physiological Society. Compr Physiol 12: 1-31, 2022.

Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.

Impaired endothelial insulin signaling and consequent blunting of insulin-induced vasodilation is a feature of type 2 diabetes (T2D) that contributes to vascular disease and glycemic dysregulation. However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, we tested the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of heat shock protein 72 (HSP72). HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, we further hypothesized that, in individuals with T2D, 7 days of passive heat treatment via hot water immersion to waist level would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. In contrast, we found that: 1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and venous endothelial cells, respectively; 2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; and 3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling, respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving leg blood flow responses to glucose ingestion-induced hyperinsulinemia.

SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice.

Aging of the vasculature is characterized by endothelial dysfunction and arterial stiffening, two key events in the pathogenesis of cardiovascular disease (CVD). Treatment with sodium glucose transporter 2 (SGLT2) inhibitors is now known to decrease cardiovascular morbidity and mortality in type 2 diabetes. However, whether SGLT2 inhibition attenuates vascular aging is unknown. We first confirmed in a cohort of adult subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether SGLT2 inhibition with empagliflozin (Empa) ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. Specifically, we assessed mesenteric artery endothelial function and stiffness (via flow-mediated dilation and pressure myography mechanical responses, respectively) and aortic stiffness (in vivo via pulse wave velocity and ex vivo via atomic force microscopy) in Empa-treated (14 mg/kg/day for 6 weeks) and control 80-week-old C57BL/6 J male mice. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Additionally, Empa-treated mice had greater vascular endothelial nitric oxide synthase activation, lower phosphorylated cofilin, and filamentous actin content, with downregulation of pathways involved in production of reactive oxygen species. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of CVD in older individuals.

Role of the Autonomic Nervous System in the Hemodynamic Response to Hyperinsulinemia-Implications for Obesity and Insulin Resistance.

PURPOSE OF REVIEW: Herein, we summarize recent advances which provide new insights into the role of the autonomic nervous system in the control of blood flow and blood pressure during hyperinsulinemia. We also highlight remaining gaps in knowledge as it pertains to the translation of findings to relevant human chronic conditions such as obesity, insulin resistance, and type 2 diabetes. RECENT FINDINGS: Our findings in insulin-sensitive adults show that increases in muscle sympathetic nerve activity with hyperinsulinemia do not result in greater sympathetically mediated vasoconstriction in the peripheral circulation. Both an attenuation of α-adrenergic-receptor vasoconstriction and augmented ß-adrenergic vasodilation in the setting of high insulin likely explain these findings. In the absence of an increase in sympathetically mediated restraint of peripheral vasodilation during hyperinsulinemia, blood pressure is supported by increases in cardiac output in insulin-sensitive individuals. We highlight a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase sympathetic nervous system activity and maintain blood pressure in insulin-sensitive adults. Whether these results translate to the insulin-resistant condition and implications for long-term cardiovascular regulation warrants further exploration.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Fitness Level- and Sex-Related Differences in Macrovascular and Microvascular Responses during Reactive Hyperemia.

PURPOSE: Reactive hyperemia (RH) is widely used for the investigation of macrovascular (flow-mediated dilation, or FMD) and microvascular (near-infrared spectroscopy-vascular occlusion test, or NIRS-VOT) function. Mixed results have been reported on fitness level- and sex-related differences in FMD outcomes, and little is known about microvascular differences in untrained and chronically trained males and females. METHODS: Fifteen chronically trained (CT: 8 males, 7 females) and 16 untrained (UT: 8 males, 8 females) individuals participated in this study. Aerobic fitness (V˙O2max) was assessed during a cycling incremental exercise test to volitional exhaustion. FMD and NIRS-VOT were performed simultaneously on the lower limb investigating superficial femoral artery and vastus lateralis muscle, respectively. RESULTS: %FMD was not different between groups (CT males, 4.62 ± 1.42; CT females, 4.15 ± 2.23; UT males, 5.10 ± 2.53; CT females, 3.20 ± 1.67). Peak blood flow showed greater values in CT versus UT (P ≤ 0.0001) and males versus females (P = 0.032). RH blood flow area under the curve was greater in CT versus UT (P = 0.001). At the microvascular level, desaturation and reperfusion rates were faster in CT versus UT (P = 0.018 and P = 0.013) and males versus females (P = 0.011 and P = 0.005). V˙O2max was significantly correlated with reperfusion rate (P = 0.0005) but not with %FMD. CONCLUSIONS: Whereas NIRS-VOT outcomes identified fitness- and sex-related differences in vascular responses, %FMD did not. However, when RH-related outcomes from the FMD analysis were considered, fitness- and/or sex-related differences were detected. These data highlight the importance of integrating FMD and NIRS-VOT outcomes for a more comprehensive evaluation of vascular function.

Responders and non-responders to aerobic exercise training: beyond the evaluation of V˙O2max.

The evaluation of the maximal oxygen uptake ( V˙O2max ) following exercise training is the classical assessment of training effectiveness. Research has lacked in investigating whether individuals that do not respond to the training intervention ( V˙O2max ), also do not improve in other health-related parameters. We aimed to investigate the cardiovascular and metabolic adaptations (i.e., performance, body composition, blood pressure, vascular function, fasting blood markers, and resting cardiac function and morphology) to exercise training among participants who showed different levels of V˙O2max responsiveness. Healthy sedentary participants engaged in a 6-week exercise training program, three times a week. Our results showed that responders had a greater increase in peak power output, second lactate threshold, and microvascular responsiveness, whereas non-responders had a greater increase in cycling efficiency. No statistical differences were observed in body composition, blood pressure, fasting blood parameters, and resting cardiac adaptations. In conclusion, our study showed, for the first time, that in addition to the differences in the V˙O2max , a greater increase in microvascular responsiveness in responders compared to non-responders was observed. Additionally, responders and non-responders did not show differences in the adaptations on metabolic parameters. There is an increasing need for personalized training prescription, depending on the target clinical outcome.

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of ß-adrenergic activation.

Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following ß-adrenergic receptor blockade. In accordance, we also reveal that insulin augments ß-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of ß-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.

Individual cardiovascular responsiveness to work-matched exercise within the moderate- and severe-intensity domains.

PURPOSE: We investigated the cardiovascular individual response to 6 weeks (3×/week) of work-matched within the severe-intensity domain (high-intensity interval training, HIIT) or moderate-intensity domain (moderate-intensity continuous training, MICT). In addition, we analyzed the cardiovascular factors at baseline underlying the response variability. METHODS: 42 healthy sedentary participants were randomly assigned to HIIT or MICT. We applied the region of practical equivalence-method for identifying the levels of responders to the maximal oxygen uptake (V̇O2max) response. For investigating the influence of cardiovascular markers, we trained a Bayesian machine learning model on cardiovascular markers. RESULTS: Despite that HIIT and MICT induced significant increases in V̇O2max, HIIT had greater improvements than MICT (p < 0.001). Greater variability was observed in MICT, with approximately 50% classified as "non-responder" and "undecided". 20 "responders", one "undecided" and no "non-responders" were observed in HIIT. The variability in the ∆V̇O2max was associated with initial cardiorespiratory fitness, arterial stiffness, and left-ventricular (LV) mass and LV end-diastolic diameter in HIIT; whereas, microvascular responsiveness and right-ventricular (RV) excursion velocity showed a significant association in MICT. CONCLUSION: Our findings highlight the critical influence of exercise-intensity domains and biological variability on the individual V̇O2max response. The incidence of "non-responders" in MICT was one third of the group; whereas, no "non-responders" were observed in HIIT. The incidence of "responders" was 11 out of 21 participants in MICT, and 20 out of 21 participants in HIIT. The response in HIIT showed associations with baseline fitness, arterial stiffness, and LV-morphology; whereas, it was associated with RV systolic function in MICT.

Rolling massage acutely improves skeletal muscle oxygenation and parameters associated with microvascular reactivity: The first evidence-based study.

Although it has been claimed that rolling massage (RM), may lead to improvements in skeletal muscle oxygenation, metabolism, blood flow, and vascular function, scientific evidence has not yet been provided. Thus, the current study investigated the effects of 30 s and 2 min of RM on forearm muscle oxygenation, parameters associated with oxidative metabolism, and microvascular reactivity as well as brachial artery endothelial function. Forearm skeletal muscle parameters were assessed in 12 healthy young men (26 ± 6 yrs) using near-infrared spectroscopy (NIRS) combined with a 5-min vascular occlusion test. Additionally, brachial artery endothelial function was simultaneously assessed by measuring the relative change in brachial artery diameter normalized to the hyperemic blood flow (Normalized %FMD). These measurements were performed before and after the RM interventions performed on the anterior forearm muscles. Forearm muscle oxygenation increased after 30 s of RM (62 ± 7 to 71 ± 11%; p = 0.02) while there was no change from baseline to post-intervention after 2 min of RM. No change was observed for oxidative metabolism, however, the significant main effect (p = 0.02) for NIRS-derived reperfusion slope (%·s-1) indicated that microvascular function improved after both 30 s (2.30 ± 0.5 to 2.61 ± 0.70%·s-1) and 2 min of RM (2.33 ± 0.4 to 2.60 ± 0.85%·s-1). The lack of significant effects of RM on Normalized %FMD suggest that the RM did not acutely improve brachial artery endothelial function. These findings provide, for the first time, evidence that RM improves skeletal muscle oxygenation and parameters associated with microvascular reactivity. Additionally, RM increased brachial artery blood flow, but not upstream brachial artery endothelial function.

Sympathetically mediated increases in cardiac output, not restraint of peripheral vasodilation, contribute to blood pressure maintenance during hyperinsulinemia.

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

Acute application of a transdermal nitroglycerin patch protects against prolonged forearm ischemia-induced microvascular dysfunction.

INTRODUCTION: Prolonged limb blood flow occlusion (ie, tourniquet application during limb surgery) causes transient microvascular dysfunction. We examined the ability of a local nitric oxide donor (transdermal nitroglycerin) administered during prolonged cuff forearm occlusion to protect against microvascular dysfunction and to alter brachial artery dilation. METHODS: Ten healthy men (28 ± 8 years) participated in the study. During the control visit, they completed three vascular occlusion tests in the right arm termed, PRE (5-min occlusion), POSTimmediate (20-min occlusion), and POST30min (5-min occlusion). During the nitroglycerin visit, subjects completed the same vascular occlusion tests, but with a nitroglycerin patch placed over the contralateral forearm during the 20-min occlusion test. Micro- and macrovascular function were assessed using the near-infrared spectroscopy-derived reperfusion upslope (reperfusion slope, %.s-1 ) and flow-mediated dilation (%FMD), respectively. RESULTS: The reperfusion slope (1.44 ± 0.72%.s-1 ) and the %FMD (15.0 ± 2.8%) of the POSTimmediate test of the nitroglycerin condition were significantly (P < .05) higher than the reperfusion slope (1.01 ± 0.37%.s-1 ) and %FMD (6.77 ± 1.8%) during the POSTimmediate test of the control visit. CONCLUSION: Transdermal nitroglycerin protects against ischemia-induced microvascular dysfunction and causes marked dilation of the brachial artery %FMD.

Effects of a rehabilitation program on microvascular function of CHD patients assessed by near-infrared spectroscopy.

This study aimed to evaluate whether near-infrared spectroscopy (NIRS)-derived reperfusion slope would detect the effects of a 12-week rehabilitation program on lower limb microvascular responsiveness in patients with coronary heart disease (CHD). Ten CHD patients (7 males and 3 females; 57.3 ± 7.6 years) underwent 12 weeks of drug treatment and high-intensity interval training (HIIT), 2 times per week (40 min/session). Microvascular responsiveness was assessed by using NIRS assessment of muscle oxygen saturation (StO2 ) combined with a vascular occlusion test (VOT) (NIRS-VOT). NIRS-VOT measures were taken at pre- and postintervention, and microvascular responsiveness was evaluated by examining the slope 2 of re-oxygenation rate (slope 2 StO2 ) and the area under the curve (StO2AUC ) of StO2 signal following cuff release subsequent to a 5-min occlusion period. The slope 2 StO2 was significantly steeper after 12 weeks of training (4.8 ± 1.6% sec-1 ) compared to the pretraining (3.1 ± 1.6% sec-1 ) (P < 0.05). The area under the curve for the change in the % StO2 signal during re-oxygenation increased significantly from 3494 ± 2372%∙sec at pretraining to 9006 ± 4311%∙sec at post-training (P < 0.05). NIRS-VOT technique detected the improvements of 12 weeks of rehabilitation program in the lower limb microvascular responsiveness of CHD patients.

Near-infrared spectroscopy detects transient decrements and recovery of microvascular responsiveness following prolonged forearm ischemia.

BACKGROUND: Impairments at the microvascular level might lead to more overt cardiovascular complications, therefore, being able to early detect microvascular dysfunction would be beneficial. Thus, the present study investigated whether near-infrared spectroscopy (NIRS) assessment of microvascular responsiveness (reoxygenation slope, %.s-1) would detect the detrimental effects on the forearm microvasculature following a period of arterial occlusion. Similarly, the effects of prolonged forearm ischemia on brachial artery function were also assessed by flow-mediated dilation (%FMD). METHODS: Fourteen individuals were tested before (Pre), immediately after (PostPI), 30 min after (Post30), and 60 min after (Post60) prolonged forearm ischemia. The Pre, Post30, and Post60 interventions consisted of 5 min of blood flow occlusion, whereas the postPI involved a 20-min occlusion period. RESULTS: The reoxygenation slope was reduced at PostPI (1.33 ±â€¯0.72%.s-1 vs. 1.79 ±â€¯0.68%.s-1 Pre; p < 0.05), but not at Post30 (1.93 ±â€¯0.70%.s-1) and Post60 (1.87 ±â€¯0.85%.s-1) (both p > 0.05 vs. Pre). Similarly, the brachial FMD response was reduced at PostPI (7.4 ±â€¯3.9% vs. 10.9 ±â€¯2.9% Pre; p < 0.05), but not at Post30 (11.3 ±â€¯4.1%) or Post60 (11.8 ±â€¯4.3%) (both p > 0.05 vs. Pre). CONCLUSION: These findings show that NIRS-derived reoxygenation slope detects the transient detrimental effects of prolonged ischemia within the forearm microvasculature. Additionally, this study found that the reduction in forearm microvascular responsiveness might have contributed to the decreased brachial artery FMD responsiveness.

The association between near-infrared spectroscopy-derived and flow-mediated dilation assessment of vascular responsiveness in the arm.

INTRODUCTION: Following a period of blood flow occlusion, the near-infrared spectroscopy (NIRS)-derived reperfusion slope of the oxygen saturation signal (StO2) is a measure of microvascular responsiveness that has been shown to be positively correlated with flow-mediated dilation (FMD) assessment of conduit artery function in the lower limb vasculature. Given that previously established differences in structure and function of the vessels in the upper compared to the lower limbs may change this relationship, investigating whether this correlation between the reperfusion slope of the StO2 and the FMD response is maintained in upper limbs is important. Accordingly, this study investigated the correlation between the reperfusion slope of the StO2 and FMD in the arm vasculature. METHODS: 18 physically active individuals were submitted to a vascular occlusion test (VOT). Microvascular responsiveness was calculated as the NIRS-derived reperfusion slope assessed in a forearm muscle. Macrovascular responsiveness was assessed at the brachial artery and calculated as a percent of change in FMD (%FMD). RESULTS: A statistically significant correlation (r = 0.66; P = 0.001) was found between the reperfusion slope and %FMD response. CONCLUSION: The significant correlation between the reperfusion slope in the forearm muscle and %FMD in the brachial artery, reinforces the relationship between downstream and upstream vascular reactivity in healthy human limbs.

Reliability of microvascular responsiveness measures derived from near-infrared spectroscopy across a variety of ischemic periods in young and older individuals.

BACKGROUND: Cardiovascular disease (CVD) is associated with impairments in microvascular responsiveness. Therefore, reliably assessing microvascular function is clinically relevant. Thus, this study aimed to examine the reliability of the near-infrared spectroscopy (NIRS)-derived oxygen saturation (StO2) reperfusion slope, a measure of microvascular responsiveness, to four different vascular occlusion tests (VOT) of different durations in young and older participants. METHODS: Eight healthy young (29 ±â€¯5 yr) and seven older (67 ±â€¯4 yr) men participated in four NIRS combined with VOT (NIRS-VOT; 30 s, 1, 3, and 5 min) in the leg microvasculature on two visits separated by 1-2 weeks. Vascular responsiveness was determined by the StO2 reperfusion slope. The coefficient of variation (CV), repeatability, reliability (ICC), and the limits of agreement (LOA) were calculated for the NIRS-derived reperfusion slopes for each occlusion duration and visit. RESULTS: CV for the StO2 reperfusion slope following 30 s, 1, 3 and 5 min of occlusion were 33 ±â€¯29%, 19 ±â€¯21%, 14 ±â€¯12%, and 12 ±â€¯10%, respectively. Repeatability values following 30 s, 1, 3 and 5 min occlusions were 20%, 1%, 4% and 21%, respectively. The ICC for the StO2 reperfusion slopes for each occlusion duration were 0.29, 0.42, 0.84, and 0.88 following 30 s, 1, 3 and 5 min of occlusion, respectively. LOA values between visit 1 and 2 for occlusions were not different from zero. There were no age-related differences for all variables of the study. CONCLUSION: NIRS-derived StO2 reperfusion slope, has good reliability across a range of occlusion durations with the strongest reliability during longer occlusion durations.

Differences in oxidative metabolism modulation induced by ischemia/reperfusion between trained and untrained individuals assessed by NIRS.

Endurance training is associated with skeletal muscle adaptations that regulate the oxidative metabolism during ischemia/reperfusion. The aim of this study was to noninvasively assess in vivo differences in the oxidative metabolism activity during ischemia/reperfusion between trained and untrained individuals, using near infrared spectroscopy (NIRS) combined with a vascular occlusion test (VOT) technique (NIRS-VOT). Sixteen untrained (26.3 ± 5.1 year) and seventeen trained (29.4 ± 4.9 year) healthy young adult men were submitted to a VOT (2 min baseline, 5 min occlusion, and 8 min reperfusion). Oxygen utilization was estimated from the area under the curve of the NIRS-derived deoxyhemoglobin [HHb] signal during occlusion (AUCocc). Muscle reperfusion was derived from the area above the curve (AACrep) of the [HHb] signal after cuff release. The AUCocc of the untrained participants (21010 ± 9553 % · s) was significantly larger than the AUCocc of their trained counterparts (12320 ± 3283 % · s); P = 0.001). The AACrep of the untrained participants (5928 ± 3769 % · s) was significantly larger than the AACrep of the trained participants (3745 ± 1900 % · s; P = 0.042). There was a significant correlation between AUCocc and AACrep (r = 0.840; P = 0.001). NIRS assessment of oxidative metabolism showed that trained individuals are more efficient in shifting between oxidative and anaerobic metabolism in response to ischemia and reperfusion.