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Fractional flow reserve (FFR) measurements are recommended for assessing hemodynamic coronary stenosis severity. Intracoronary ECG (icECG) is easily obtainable and highly sensitive in detecting myocardial ischemia due to its close vicinity to the myocardium. We hypothesized that the remission time of myocardial ischemia on icECG after a controlled coronary occlusion accurately detects hemodynamically relevant coronary stenosis. This retrospective, observational study included patients with chronic coronary syndrome undergoing hemodynamic coronary stenosis assessment immediately following a strictly 1-min proximal coronary artery balloon occlusion with simultaneous icECG recording. icECG was used for a beat-to-beat analysis of the ST-segment shift during reactive hyperemia immediately following balloon deflation. The time from coronary balloon deflation until the ST-segment shift reached 37% of its maximum level, i.e., icECG ST-segment shift remission time (τ-icECG in seconds), was obtained by an automatic algorithm. τ-icECG was tested against the simultaneously obtained reactive hyperemia FFR at a threshold of 0.80 as a reference parameter. From 120 patients, 139 icECGs (age, 68 ± 10 yr old) were analyzed. Receiver operating characteristic (ROC) analysis of τ-icECG for the detection of hemodynamically relevant coronary stenosis at an FFR of ≤0.80 was performed. The area under the ROC curve was equal to 0.621 ( P = 0.0363) at an optimal τ-icECG threshold of 8 s (sensitivity, 61%; specificity, 67%). τ-icECG correlated inversely and linearly with FFR ( P = 0.0327). This first proof-of-concept study demonstrates that τ-icECG, a measure of icECG ST segment-shift remission after a 1-min coronary artery balloon occlusion accurately detects hemodynamically relevant coronary artery stenosis according to FFR at a threshold of ≥8 s. NEW & NOTEWORTHY Invasive hemodynamic measurements are recommended by the current cardiology guidelines to guide percutaneous coronary interventions in the setting of chronic coronary syndrome. However, those pressure-derived indices demonstrate several theoretical and practical limitations. Thus, this study demonstrates the accuracy of a novel, pathophysiology-driven approach using intracoronary ECG for the identification of hemodynamically relevant coronary lesions by quantitatively assessing myocardial ischemia remission.

Peripheral microvascular dysfunction has been documented in patients with heart failure with preserved ejection fraction (HFpEF), which may be related to elevated levels of inflammation and oxidative stress. Unfortunately, few strategies have been identified to effectively ameliorate this disease-related derangement. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on lower limb microvascular reactivity, functional capacity, and biomarkers of inflammation and oxidative stress in patients with HFpEF (statin, n = 8, 76 ± 6 yr; placebo, n = 8, 68 ± 9 yr). The passive limb movement (PLM)-induced hyperemic response and 6-min walk test (6MWT) distance were evaluated to assess ambulatory muscle microvascular function and functional capacity, respectively. Circulating biomarkers were also measured to assess the contribution of changes in inflammation and redox balance to these outcomes. The total hyperemic response to PLM, assessed as leg blood flow area under the curve (LBF AUC ), increased following the statin intervention (pre, 60 ± 68 mL; post, 164 ± 90 mL; P < 0.01), whereas these variables were unchanged in the placebo group ( P = 0.99). There were no significant differences in 6MWT distance following statin or placebo intervention. Malondialdehyde (MDA), a marker of lipid peroxidation, was significantly reduced following the statin intervention (pre, 0.68 ± 0.10; post, 0.51 ± 0.11; P < 0.01) while other circulating biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to a diminution in oxidative stress. NEW & NOTEWORTHY This was the first study to investigate the impact of statin administration on locomotor muscle microvascular function in patients with HFpEF. In support of our hypothesis, the total hyperemic response to PLM, assessed as leg blood flow area under the curve, increased, and malondialdehyde, a marker of oxidative damage, was reduced following the statin intervention. Together, these data provide new evidence for the efficacy of statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to reduced oxidative stress.

The near-infrared spectroscopy (NIRS) vascular occlusion test (VOT) assesses microvascular reperfusion. Two strategies have been used to quantify reperfusion following reactive hyperemia, but it is unclear whether both yield similar results when comparing biological sex. This study aimed to determine whether sex differences in NIRS-based microvascular reperfusion are similarly apparent using the 10-s reactive hyperemia slope of the tissue saturation index (StO 2 ) signal (slope 2) and the halftime to maximal reperfusion (T ½). Healthy, recreationally active males ( n = 31) and females ( n = 31) between 18 and 82 years took part in this study. A NIRS VOT was performed on the tibialis anterior muscle, and reperfusion was quantified using slope 2 (% s -1 ) and T ½ (s). Adipose tissue thickness (ATT) was higher in females ( P = 0.009), which was associated with a lower StO 2 ( P = 0.001) and oxygenated hemoglobin (O 2 Hb) ( P = 0.05) signal range. The StO 2 slope 2 was significantly steeper in males versus females ( P = 0.001) but not after correcting for ATT ( P = 0.295). There were no sex differences in StO 2 T ½ ( P = 0.067) or O 2 Hb T ½ ( P = 0.197). In a subset of males ( n = 26) and females ( n = 21) with similar ATT, there were no sex differences in StO 2 slope 2 ( P = 0.068), StO 2 T ½ ( P = 0.491), or O 2 Hb T ½ ( P = 0.899). An ATT-corrected StO 2 slope 2 or the T ½ approach is recommended for analysis of NIRS-based microvascular reperfusion when differences in ATT are present between sexes. NEW & NOTEWORTHY Sex differences in near-infrared spectroscopy (NIRS)-based microvascular reperfusion have been previously reported. We found that greater adipose tissue thickness in females reduces kinetic measures of NIRS-based microvascular reperfusion. Sex differences are eliminated when performing an adipose tissue thickness correction, when the NIRS signal range is accounted for, or when adipose tissue thickness is similar between sexes. This highlights the importance of considering factors that affect NIRS signals, such as adipose tissue thickness, when drawing comparisons between groups.

Near-infrared spectroscopy combined with vascular occlusion test (NIRS-VOT) is a reactive hyperemia technique for in vivo evaluation of skeletal muscle microvascular reactivity. Previous studies using NIRS-VOT have been shown to be able to detect impairments in microvascular function in high-risk cardiovascular disease populations, such as older individuals. It has been demonstrated that older individuals have slower reactive hyperemia compared with young individuals. Importantly, older individuals also show less desaturation during ischemia compared with young individuals. Based on these findings, it has been suggested that the slower reactive hyperemia observed in older individuals is explained by the lower desaturation during blood flow occlusion (reduced ischemic stimulus). This retrospective analysis compared reactive hyperemia in 36 young and 47 older tissue desaturation-matched individuals that underwent 5-min blood flow occlusion. Overall, we showed that older individuals have impaired reactive hyperemia compared with young when matching for the degree of desaturation and blood flow occlusion time. These findings provide evidence that lower tissue desaturation during ischemia is not a major determinant of impaired reactive hyperemia in older individuals. NEW & NOTEWORTHY Previous findings have suggested that aging-related impairment in skeletal muscle reactive hyperemia is majorly influenced by a lower degree of tissue desaturation during ischemia in older individuals compared with young individuals. In a retrospective analysis including 83 tissue desaturation-matched individuals, we show that the degree of tissue desaturation is not a major determinant of aging-related impairments in reactive hyperemia.

Aging is associated with inspiratory muscle dysfunction; however, the impact of aging on diaphragm blood flow (BF) regulation, and whether sex differences exist, is unknown. We tested the hypotheses in young animals that diaphragm BF and vascular conductance (VC) would be greater in females and that aging would decrease the diaphragm's ability to increase BF with contractions. Young (4-6 mo) and old (22-24 mo) Fischer 344 rats were divided into four groups: young female (YF, n = 7), young male (YM, n = 8), old female (OF, n = 9), and old male (OM, n = 9). Diaphragm BF (mL/min/100 g) and VC (mL/mmHg/min/100 g) were determined, via fluorescent microspheres, at rest and during 1 Hz contractions. In YF versus OF, aging blunted the increase in medial costal diaphragm BF (44 ± 5% vs. 16 ± 12%; P < 0.05) and VC (43 ± 7% vs. 21 ± 12%; P < 0.05). Similarly, in YM versus OM, aging blunted the increase in medial costal diaphragm BF (43 ± 6% vs. 24 ± 12%; P < 0.05) and VC (50 ± 6% vs. 34 ± 10%; P < 0.05). In female rats, age increased dorsal costal diaphragm BF, whereas in male rats, age increased crural diaphragm BF ( P < 0.05). Compared with age-matched females, dorsal costal diaphragm BF was lower in YM and OM ( P < 0.05). In conclusion, aging results in an inability to augment medial costal diaphragm BF and alters regional diaphragm BF distribution in response to muscular contractions. Furthermore, sex differences in regional diaphragm BF are present in young and old animals. NEW & NOTEWORTHY This is the first study, to our knowledge, to demonstrate that old age impairs the hyperemic response and alters blood flow distribution in the diaphragm of both female and male rats. In addition, this investigation provides novel evidence of sex differences in regional diaphragm blood flow distribution with contractions. The data presented herein suggest that aging compromises diaphragm vascular function and provides a potential mechanism for the diaphragm contractile dysfunction associated with old age.

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 (So 2deficit , 3,810 ± 1,420 vs. 2,723 ± 1,240%s) during ischemia, as well as oxygen resaturation kinetics (So 2slope , 2.5 ± 0.7 vs. 1.7 ± 0.7%s -1 ) upon reperfusion (all P < 0.05). When OE in the young and So 2slope 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 So 2slope 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.

Transient receptor potential vanilloid 4 (TRPV4) channels exist on vascular endothelial cells and eccrine sweat gland secretory cells in human skin. Here, we assessed whether TRPV4 channels contribute to cutaneous vasodilation and sweating during whole body passive heat stress ( protocol 1 ) and to cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia ( protocol 2 ). Intradermal microdialysis was employed to locally deliver pharmacological agents to forearm skin sites, where cutaneous vascular conductance (CVC) and sweat rate were assessed. In protocol 1 (12 young adults), CVC and sweat rate were increased by passive whole body heating, resulting in a body core temperature elevation of 1.2 ± 0.1°C. The elevated CVC and sweat rate assessed at sites treated with TRPV4 channel antagonist (either 200 µM HC-067047 or 125 µM GSK2193874) were not different from the vehicle control site (5% dimethyl sulfoxide). After whole body heating, the TRPV4 channel agonist (100 µM GSK1016790A) was administered to each skin site, eliciting elevations in CVC. Relative to control, this response was partly attenuated by both TRPV4 channel antagonists, confirming drug efficacy. In protocol 2 (10 young adults), CVC was increased following a 5-min arterial occlusion and during local heating from 33 to 42°C. These responses did not differ between the control and the TRPV4 channel antagonist sites (200 µM HC-067047). We show that TRPV4 channels are not required for regulating cutaneous vasodilation or sweating during a whole body passive heat stress. Furthermore, they are not required for regulating cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia.

Pannexin 1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contribute to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to metabolic demand of tissue. Male and female mice devoid of Panx1 ( Panx1 -/- ) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1 -/- erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1 -/- ( n = 6) and WT ( n = 6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1 -/- mice (-16 ± 9% vs. -2 ± 8%; P < 0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1 -/- ( n = 6) vs. WT ( n = 6) basally, and increased in WT but not Panx1 -/- mice during hypoxia (8 ± 6% vs. -10 ± 13%; P < 0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs. -9% for Panx1 -/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1 -/- ( n = 6) vs. WT mice ( n = 6; P < 0.05). Mean hypoxia-induced ATP export from RBCs from Panx1 -/- mice ( n = 8) was 82% lower than that from WT ( n = 8; P < 0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood. NEW & NOTEWORTHY Export of vasodilator ATP from red blood cells requires pannexin 1. Blood plasma ATP elevations in response to hypoxia in mice require pannexin 1. Hemodynamic responses to hypoxia are accompanied by increased plasma ATP in mice in vivo and require pannexin 1.

While SARS-CoV-2 primarily affects the lungs, the virus may be inflicting detriments to the cardiovascular system, both directly through angiotensin-converting enzyme 2 receptor and initiating systemic inflammation. Persistent systemic inflammation may be provoking vascular dysfunction, an early indication of cardiovascular disease risk. To establish the potential effects of SARS-CoV-2 on the systemic vasculature in the arms and legs, we performed a cross-sectional analysis of young healthy adults (control: 5 M/15 F, 23.0 ± 1.3 y, 167 ± 9 cm, 63.0 ± 7.4 kg) and young adults who, 3-4 wk prior to testing, had tested positive for SARS-CoV-2 (SARS-CoV-2: 4 M/7 F, 20.2 ± 1.1 y, 172 ± 12 cm, 69.5 ± 12.4 kg) (means ± SD). Using Doppler ultrasound, brachial artery flow-mediated dilation (FMD) in the arm and single passive limb movement (sPLM) in the leg were assessed as markers of vascular function. Carotid-femoral pulse wave velocity (PWVcf) was asvsessed as a marker of arterial stiffness. FMD was lower in the SARS-CoV-2 group (2.71 ± 1.21%) compared with the control group (8.81 ± 2.96%) ( P < 0.01) and when made relative to the shear stimulus (SARS-CoV-2: 0.04 ± 0.02 AU, control: 0.13 ± 0.06 AU, P < 0.01). The femoral artery blood flow response, as evidenced by the area under the curve, from the sPLM was lower in the SARS-CoV-2 group (-3 ± 91 mL) compared with the control group (118 ± 114 mL) ( P < 0.01). PWVcf was higher in the SARS-CoV-2 group (5.83 ± 0.62 m/s) compared with the control group (5.17 ± 0.66 m/s) ( P < 0.01). Significantly lower systemic vascular function and higher arterial stiffness are evident weeks after testing positive for SARS-CoV-2 among young adults compared with controls. NEW & NOTEWORTHY This study was the first to investigate the vascular implications of contracting SARS-CoV-2 among young, otherwise healthy adults. Using a cross-sectional design, this study assessed vascular function 3-4 wk after young adults tested positive for SARS-CoV-2. The main findings from this study were a strikingly lower vascular function and a higher arterial stiffness compared with healthy controls. Together, these results suggest rampant vascular effects seen weeks after contracting SARS-CoV-2 in young adults.

Patients with type 2 diabetes mellitus (T2DM) exhibit diminished exercise capacity likely attributable to reduced skeletal muscle blood flow (i.e., exercise hyperemia). A potential underlying mechanism of the impaired hyperemic response to exercise could be inadequate blunting of sympathetic-mediated vasoconstriction (i.e., poor functional sympatholysis). Therefore, we studied the hyperemic and vasodilatory responses to handgrip exercise in patients with T2DM as well as vasoconstriction to selective α-agonist infusion. Forearm blood flow (FBF) and vascular conductance (FVC) were examined in patients with T2DM ( n = 30) as well as nondiabetic controls ( n = 15) with similar age (59 ± 9 vs. 60 ± 9 yr, P = 0.69) and body mass index (31.4 ± 5.2 vs. 29.5 ± 4.6 kg/m 2 , P = 0.48). Intra-arterial infusion of phenylephrine (α 1 -agonist) and dexmedetomidine (α 2 -agonist) were used to induce vasoconstriction: [(FVC with drug - FVC predrug )/FVC predrug × 100%]. Subjects completed rest and dynamic handgrip exercise (20% of maximum) trials per α-agonist. Patients with T2DM had smaller increases (Δ from rest) in FBF (147 ± 71 vs. 199 ± 63 ml/min) and FVC (126 ± 58 vs. 176 ± 50 ml·min -1 ·100 mmHg -1 , P < 0.01 for both) during exercise compared with controls, respectively. During exercise, patients with T2DM had greater α 1 - (-16.9 ± 5.9 vs. -11.3 ± 3.8%) and α 2 -mediated vasoconstriction (-23.5 ± 7.1 vs. -19.0 ± 6.5%, P < 0.05 for both) versus controls. The magnitude of sympatholysis (Δ in %vasoconstriction between exercise and rest) for PE was lower (worse) in patients with T2DM versus controls (14.9 ± 12.2 vs. 23.1 ± 8.1%, P < 0.05) whereas groups were similar during DEX trials (24.6 ± 12.3 vs. 27.6 ± 13.4%, P = 0.47). Our data suggest patients with T2DM have attenuated hyperemic and vasodilatory responses to exercise, which could be attributable to greater α 1 -mediated vasoconstriction in contracting skeletal muscle. NEW & NOTEWORTHY Findings presented in this article are the first to show patients with type 2 diabetes mellitus have blunted hyperemic and vasodilatory responses to dynamic handgrip exercise. Moreover, we illustrate greater α 1 -adrenergic-mediated vasoconstriction may contribute to our initial observations. Collectively, these data suggest patients with type 2 diabetes may have impaired functional sympatholysis, which can contribute to their reduced exercise capacity.

Microvascular dysfunction often precedes other age-related macrovascular conditions and predicts future cardiovascular risk. Sirtuin 1 (Sirt1) has recently emerged as a protein that protects the vasculature and reduces the risk of cardiovascular diseases. We tested the hypothesis that lower Sirt1 during childhood is associated with a reduced microvascular function during adulthood. Thirty-four adults (34 ± 3 yr) from the Augusta Heart Study returned to participate in the present clinical observational study. Sirt1 was assessed in samples collected during both adulthood and participants' childhood (16 ± 3 yr), and data were divided based on childhood Sirt1 concentrations: <3 ng/dL (LowCS; n = 16) and ≥3 ng/dL (HighCS; n = 18). MVF was evaluated in all of the adults using laser-Doppler flowmetry coupled with three vascular reactivity tests: 1 ) local thermal hyperemia (LTH), 2 ) post-occlusive reactive hyperemia (PORH), and 3 ) iontophoresis of acetylcholine (ACh). The hyperemic response to LTH was significantly ( P ≤ 0.044) lower in the LowCS than in the HighCS group. Similarly, the LowCS also exhibited an ameliorated ( P ≤ 0.045) response to the PORH test and lower ( P ≤ 0.008) vasodilation in response to iontophoresis of ACh when compared with the HighCS. Positive relationships were identified between childhood Sirt1 and all MVF reactivity tests ( r ≥0.367, P ≤ 0.004). Novel observations suggest that lower Sirt1 during childhood is associated with premature microvascular dysfunction in adulthood. These findings provide evidence that Sirt1 may play a critical role in microvascular function and have therapeutic potential for the prevention of age-associated vascular dysfunction in humans. NEW & NOTEWORTHY With a longitudinal cohort, novel observations from the present study demonstrate that individuals who had lower Sirt1 early in life exhibit premature microvascular dysfunction during adulthood and may be at higher risk to develop CVD. These results provide experimental evidence that Sirt1 may play an important role in microvascular function with age and represent a potential therapeutic target to prevent premature vascular dysfunction.

Reactive hyperemia is a well-established technique for noninvasive assessment of peripheral microvascular function and a predictor of all-cause and cardiovascular morbidity and mortality. In its simplest form, reactive hyperemia represents the magnitude of limb reperfusion following a brief period of ischemia induced by arterial occlusion. Over the past two decades, investigators have employed a variety of methods, including brachial artery velocity by Doppler ultrasound, tissue reperfusion by near-infrared spectroscopy, limb distension by venous occlusion plethysmography, and peripheral artery tonometry, to measure reactive hyperemia. Regardless of the technique used to measure reactive hyperemia, blunted reactive hyperemia is believed to reflect impaired microvascular function. With the advent of several technological advancements, together with an increased interest in the microcirculation, reactive hyperemia is becoming more common as a research tool and is widely used across multiple disciplines. With this in mind, we sought to review the various methodologies commonly used to assess reactive hyperemia and current mechanistic pathways believed to contribute to reactive hyperemia and reflect on several methodological considerations.

Local skin heating to 42°C causes cutaneous thermal hyperemia largely via nitric oxide (NO) synthase (NOS)-related mechanisms. We assessed the hypothesis that ATP-sensitive K + (K ATP ) channels interact with NOS to mediate cutaneous thermal hyperemia. In 13 young adults (6 women, 7 men), cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with 1 ) lactated Ringer solution (control), 2 ) 5 mM glibenclamide (K ATP channel blocker), 3 ) 20 mM N G -nitro-l-arginine methyl ester (NOS inhibitor), or 4 ) a combination of K ATP channel blocker and NOS inhibitor. Local skin heating to 42°C was administered at all four treatment sites to elicit cutaneous thermal hyperemia. Thirty minutes after the local heating, 1.25 mM pinacidil (K ATP channel opener) and subsequently 25 mM sodium nitroprusside (NO donor) were administered to three of the four sites (each 25-30 min). The local heating-induced prolonged elevation in CVC was attenuated by glibenclamide (19%), but the transient initial peak was not. However, glibenclamide had no effect on the prolonged elevation in CVC in the presence of NOS inhibition. Pinacidil caused an elevation in CVC, but this response was abolished at the glibenclamide-treated skin site, demonstrating its effectiveness as a K ATP channel blocker. The pinacidil-induced increase in CVC was unaffected by NOS inhibition, whereas the increase in CVC elicited by sodium nitroprusside was partly (15%) inhibited by glibenclamide. In summary, we showed an interactive effect of K ATP channels and NOS for the plateau of cutaneous thermal hyperemia. This interplay may reflect a vascular smooth muscle cell K ATP channel activation by NO.

The mechanisms underlying reactive hyperemia (RH) responses in microvessels are poorly understood. Previous assessment tools have not been capable of directly visualizing microvessels during physiological stimulation in humans. Optical coherence tomography (OCT) is capable of imaging and quantifying subcutaneous microvessels as small as ~30 µm. In this study we use OCT to visualize and quantify skin microvascular changes in response to RH for the first time in humans. We also assessed the reproducibility of this technique. OCT and laser Doppler flowmetry (LDF) were used simultaneously to scan cutaneous microvessels in 10 young healthy subjects on 2 days. We applied a speckle decorrelation algorithm to assess OCT images and calculated flow rate, speed, diameter, and density parameters. Measures were obtained at rest (baseline) and 30-s following a 5-min cuff inflation (RH). All data were compared between days. The RH stimulus significantly increased ( P < 0.0001) OCT-derived microvascular diameter (37.6 ± 3.4 vs. 44.5 ± 5.2 µm), flow rate (82.4 ± 23.4 vs. 240.1 ± 58.6 pl/s), speed (48 ± 5.7 vs. 101.5 ± 17.1 µm/s), density (5.1 ± 1.7 vs. 14.6 ± 2.6%), and also LDF-derived flux (12.3 ± 5.7 vs. 31.6 ± 9.1 perfusion units). At baseline, OCT-derived diameter ( r  = 0.55), flow rate ( r  = 0.64), speed ( r  = 0.55), and density ( r  = 0.75) showed significant between-day correlations ( P < 0.05), as did LDF results ( r  = 0.74). In response to RH, OCT-derived diameter ( r  = 0.63) and density ( r  = 0.64) showed significant correlations ( P < 0.05), whereas flow rate ( r  = 0.45), speed ( r  = 0.43), and LDF ( r  = 0.26) were less reproducible. Our study is novel in that it establishes the feasibility of using OCT to visualize and quantify microvascular structure and function responses to RH in humans. NEW & NOTEWORTHY This study describes the first evidence in humans that optical coherence tomography provides direct visualization and comprehensive quantification of cutaneous microvascular hemodynamics as a response to reactive hyperemia. This imaging technique will greatly improve human cutaneous microvascular assessment in physiological and clinical settings.

Although it is now well established that heart failure with preserved ejection fraction (HFpEF) is associated with marked inflammation and a prooxidant state that is accompanied by vascular dysfunction, whether acute antioxidant (AO) administration can effectively target these disease-related decrements has not been evaluated. Thus, the present study sought to evaluate the efficacy of an acute over-the-counter AO cocktail (600 mg α-lipoic acid, 1,000 mg vitamin C, and 600 IU vitamin E) to mitigate inflammation and oxidative stress, and subsequently improve nitric oxide (NO) bioavailability and vascular function, in patients with HFpEF. Flow-mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit vessel and microvascular function, respectively, 90 min after administration of either placebo (PL) or AO in 16 patients with HFpEF (73 ± 10 yr, EF 54-70%) using a double-blind, crossover design. Circulating biomarkers of inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde and protein carbonyl), free radical concentration (EPR spectroscopy), antioxidant capacity, ascorbate and NO bioavailability (plasma nitrate, [Formula: see text], and nitrite, [Formula: see text]) were also assessed. FMD improved following AO administration (PL: 3.49 ± 0.7%, AO: 5.83 ± 1.0%), whereas RH responses were similar between conditions (PL: 428 ± 51 mL, AO: 425 ± 51 mL). AO administration decreased CRP (PL: 4,429 ± 705 ng/mL, AO: 3,664 ± 520 ng/mL) and increased ascorbate (PL: 30.0 ± 2.9 µg/mL, AO: 45.1 ± 3.7 µg/mL) and [Formula: see text] (PL: 182 ± 21 nM, AO: 213 ± 24 nM) but did not affect other biomarkers. Together, these data suggest that acute AO administration can exert anti-inflammatory effects and improve conduit artery vasodilation, but not microvascular function, in patients with HFpEF.

Reactive hyperemia is an established, noninvasive technique to assess microvascular function and a powerful predictor of all-cause and cardiovascular morbidity and mortality. Emerging evidence from our laboratory suggests a close link between reactive hyperemia and the metabolic rate of the ischemic limb and the existence of large interindividual differences contributing to markedly different stimuli to vasodilate. Here we relate forearm tissue desaturation (i.e., the ischemic stimulus to vasodilate, measured by near-infrared spectroscopy) to brachial artery hyperemic velocity and flow (measured using duplex ultrasound) across a wide range of ischemic stimuli. Twelve young and 11 elderly individuals were prospectively studied. To recapitulate conventional vascular occlusion testing, reactive hyperemia was first assessed using a standard 5-min occlusion period. Then, to evaluate the dose dependence of tissue ischemia on reactive hyperemia, we randomly performed 4-, 6-, and 8-min cuff occlusions in both groups. In all cases, peak velocity, as well as the 5-s average velocity, immediately after the cuff occlusion was significantly higher in the young than the elderly group; however, tissue desaturation was also much more pronounced in the young group ( P < 0.05), representing a greater ischemic stimulus. Remarkably, when reactive hyperemia was adjusted for the ischemic vasodilatory stimulus, group differences in reactive hyperemia were abrogated. Together, these data challenge conventional interpretations of reactive hyperemia and show that the ischemic stimulus to vasodilate varies across individuals and that the level of reactive hyperemia is often coupled to the magnitude of tissue desaturation.

A large body of evidence demonstrates an independent association between arterial stiffness and prospective risk of cardiovascular events. A reduction in coronary perfusion is presumed to underscore this association; however, studies confirming this are lacking. This study compared invasive measures of coronary blood flow (CBF) with cardiac magnetic resonance (CMR)-derived aortic distensibility (AD). Following coronary angiography, a Doppler FloWire and infusion microcatheter were advanced into the study vessel. Average peak velocity (APV) was acquired at baseline and following intracoronary adenosine to derive coronary flow velocity reserve (CFVR = hyperemic APV/resting APV) and CBF [π × (diameter) 2 × APV × 0.125]. Following angiography, patients underwent CMR to evaluate distensibility at the ascending aorta (AA), proximal descending aorta (PDA) and distal descending aorta (DDA). Fifteen participants (53 ± 13 yr) with minor epicardial disease (maximum stenosis <30%) were enrolled. Resting CBF was 44.1 ± 11.9 mL/min, hyperemic CBF was 143.8 ± 37.4 mL/min, and CFVR was 3.15 ± 0.48. AD was 3.89 ± 1.72·10 -3 mmHg -1 at the AA, 4.08 ± 1.80·10 -3 mmHg -1 at the PDA, and 4.42 ± 1.67·10 -3 mmHg -1 at the DDA. All levels of distensibility correlated with resting CBF ( R 2 = 0.350-0.373, P < 0.05), hyperemic CBF ( R 2 = 0.453-0.464, P < 0.01), and CFVR ( R 2 = 0.442-0.511, P < 0.01). This study demonstrates that hyperemic and, to a lesser extent resting CBF, are significantly associated with measures of aortic stiffness in patients with only minor angiographic disease. These findings provide further in vivo support for the observed prognostic capacity of large artery function in cardiovascular event prediction. NEW & NOTEWORTHY Cardiac magnetic resonance-derived aortic distensibility is associated with invasive measures of coronary blood flow. Large artery function is more strongly correlated with hyperemic than resting blood flow. Increased stiffness may represent a potential target for novel antianginal medications.

Capillary derecruitment distal to a coronary stenosis is implicated as the mechanism of reversible perfusion defect and potential myocardial ischemia during coronary hyperemia; however, the underlying mechanisms are not defined. We tested whether pericyte constriction underlies capillary derecruitment during hyperemia under conditions of stenosis. In vivo two-photon microscopy (2PM) and optical microangiography (OMAG) were used to measure hyperemia-induced changes in capillary diameter and perfusion in wild-type and pericyte-depleted mice with femoral artery stenosis. OMAG demonstrated that hyperemic challenge under stenosis produced capillary derecruitment associated with decreased RBC flux. 2PM demonstrated that hyperemia under control conditions induces 26 ± 5% of capillaries to dilate and 19 ± 3% to constrict. After stenosis, the proportion of capillaries dilating to hyperemia decreased to 14 ± 4% ( P = 0.05), whereas proportion of constricting capillaries increased to 32 ± 4% ( P = 0.05). Hyperemia-induced changes in capillary diameter occurred preferentially in capillary segments invested with pericytes. In a transgenic mouse model featuring partial pericyte depletion, only 14 ± 3% of capillaries constricted to hyperemic challenge after stenosis, a significant reduction from 33 ± 4% in wild-type littermate controls ( P = 0.04). These results provide for the first time direct visualization of hyperemia-induced capillary derecruitment distal to arterial stenosis and demonstrate that pericyte constriction underlies this phenomenon in vivo. These results could have important therapeutic implications in the treatment of exercise-induced ischemia. NEW & NOTEWORTHY In the setting of coronary arterial stenosis, hyperemia produces a reversible perfusion defect resulting from capillary derecruitment that is believed to underlie cardiac ischemia under hyperemic conditions. We use optical microangiography and in vivo two-photon microscopy to visualize capillary derecruitment distal to a femoral arterial stenosis with cellular resolution. We demonstrate that capillary constriction in response to hyperemia in the setting of stenosis is dependent on pericytes, contractile mural cells investing the microcirculation.

Continuous passive leg movement (PLM) is a promising clinical assessment of the age-related decline in peripheral vascular function. To further refine PLM, this study evaluated the efficacy of a single PLM (sPLM), a simplified variant of the more established continuous movement approach, to delineate between healthy young and old men based on vascular function. Twelve young (26 ± 5 yr) and 12 old (70 ± 7 yr) subjects underwent sPLM (a single passive flexion and extension of the knee joint through 90°), with leg blood flow (LBF, common femoral artery with Doppler ultrasound), blood pressure (finger photoplethysmography), and leg vascular conductance (LVC) assessed. A receiver operator characteristic curve analysis was used to determine an age-specific cut score, and a factor analysis was performed to assess covariance. Baseline LBF and LVC were not different between groups ( P = 0.6). The high level of covariance and similar predictive value for all PLM-induced LBF and LVC responses indicates LBF, alone, can act as a surrogate variable in this paradigm. The peak sPLM-induced increase in LBF from baseline was attenuated in the old (Young: 717 ± 227, Old: 260 ± 97 ml/min, P < 0.001; cut score: 372 ml/min), as was the total LBF response (Young: 155 ± 67, Old: 26 ± 17 ml, P < 0.001; cut score: 58 ml). sPLM, a simplified version of PLM, exhibits the prerequisite qualities of a valid screening test for peripheral vascular dysfunction, as evidenced by an age-related attenuation in the peripheral hyperemic response and a clearly delineated age-specific cut score. NEW & NOTEWORTHY Single passive leg movement (sPLM) exhibits the prerequisite qualities of a valid screening test for peripheral vascular dysfunction. sPLM displayed an age-related reduction in the peripheral hemodynamic response for amplitude, duration, initial rate of change, and total change with clearly delineated age-specific cut scores. sPLM has a strong candidate variable that is a simple single numeric value, for which to appraise peripheral vascular function, the 45-s hyperemic response (leg blood flow area under the curve: 45 s).

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A 2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o 2 ) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA 2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o 2 , and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA 2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A 2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A 2 treatment.

The aim of this study was to compare fatigability, contractile function, and blood flow to the knee extensor muscles after dynamic exercise in patients with type 2 diabetes mellitus (T2DM) and controls. The hypotheses were that patients with T2DM would demonstrate greater fatigability than controls, and greater fatigability would be associated with a lower exercise-induced increase in blood flow and greater impairments in contractile function. Patients with T2DM ( n = 15; 8 men; 62.4 ± 9.0 yr; 30.4 ± 7.7 kg/m 2 ; 7,144 ± 3,294 steps/day) and 15 healthy control subjects (8 men, 58.4 ± 6.9 yr; 28.4 ± 4.6 kg/m 2 ; 7,893 ± 2,323 steps/day) were matched for age, sex, body mass index, and physical activity. Fatigability was quantified as the reduction in knee extensor power during a 6-min dynamic exercise. Before and after exercise, vascular ultrasonography and electrical stimulation were used to assess skeletal muscle blood flow and contractile properties, respectively. Patients with T2DM had greater fatigability (30.0 ± 20.1% vs. 14.6 ± 19.0%, P < 0.001) and lower exercise-induced hyperemia (177 ± 90% vs. 194 ± 79%, P = 0.04) than controls but similar reductions in the electrically evoked twitch amplitude (37.6 ± 24.8% vs. 31.6 ± 30.1%, P = 0.98). Greater fatigability of the knee extensor muscles was associated with postexercise reductions in twitch amplitude ( r = 0.64, P = 0.001) and lesser exercise-induced hyperemia ( r = -0.56, P = 0.009). Patients with T2DM had greater lower-limb fatigability during dynamic exercise, which was associated with reduced contractile function and lower skeletal muscle blood flow. Thus, treatments focused on enhancing perfusion and reversing impairments in contractile function in patients with T2DM may offset lower-limb fatigability and aid in increasing exercise capacity. NEW & NOTEWORTHY Although prior studies compare patients with type 2 diabetes mellitus (T2DM) with lean controls, our study includes controls matched for age, body mass, and physical activity to more closely assess the effects of T2DM. Patients with T2DM demonstrated no impairment in macrovascular endothelial function, evidenced by similar flow-mediated dilation to controls. However, patients with T2DM had greater fatigability and reduced exercise-induced increase in blood flow (hyperemia) after a lower-limb dynamic fatiguing exercise compared with controls.

Previous studies have demonstrated that African-American (AA) individuals have heightened vasoconstrictor and reduced vasodilator responses under resting conditions compared with Caucasian-American (CA) individuals. However, potential differences in vascular responses to exercise remain unclear. Therefore, we tested the hypothesis that, compared with CA subjects, AA subjects would present an attenuated increase in forearm vascular conductance (FVC) during rhythmic handgrip exercise. Forearm blood flow (FBF; duplex Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured in healthy young CA ( n = 10) and AA ( n = 10) men during six trials of rhythmic handgrip performed at workloads of 4, 8, 12, 16, 20, and 24 kg. FVC (calculated as FBF/MAP), FBF, and MAP were similar between groups at rest (FVC: 63 ± 7 ml·min -1 ·100 mmHg -1 in CA subjects vs. 62 ± 7 ml·min -1 ·100 mmHg -1 in AA subjects, P = 0.862). There was an intensity-dependent increase in FVC during exercise in both groups; however, AA subjects presented lower FVC (interaction P < 0.001) at 8-, 12-, 16-, 20-, and 24-kg workloads (e.g., 24 kg: 324 ± 20 ml·min -1 ·100 mmHg -1 in CA subjects vs. 241 ± 21 ml·min -1 ·100 mmHg -1 in AA subjects, P < 0.001). FBF responses to exercise were also lower in AA subjects (interaction P < 0.001), whereas MAP responses did not differ between groups (e.g., ∆MAP at 24 kg: +19 ± 2 mmHg in CA subjects vs. +19 ± 2 mmHg in AA subjects, interaction P = 0.950). These findings indicate lower hyperemic responses to rhythmic handgrip exercise in AA men compared with CA men. NEW & NOTEWORTHY It is known that African-American individuals have heightened vasoconstriction and reduced vasodilation under resting conditions compared with Caucasian-American individuals. Here, we identified that the hyperemic response to moderate and high-intensity rhythmic handgrip exercise was lower in healthy young African-American men.

The effect of severe burn injury on vascular health is unknown. We tested the hypothesis that, compared with nonburn control subjects, vasodilator function would be reduced and that pulse-wave velocity (a measure of arterial stiffness) would be increased in individuals with prior burn injuries, the extent of which would be associated with the magnitude of body surface area having sustained a severe burn. Pulse-wave velocity and macrovascular (flow-mediated dilation) and microvascular (reactive hyperemia) dilator functions were assessed in 14 nonburned control subjects and 32 age-matched subjects with well-healed burn injuries. Fifteen subjects with burn injuries covering 17-40% of body surface area were assigned to a moderate burn injury group, and 17 subjects with burn injuries covering >40% of body surface area were assigned to a high burn injury group. Pulse-wave velocity [ P = 0.3 (central) and P = 0.3 (peripheral)] did not differ between the three groups. Macrovascular dilator function was reduced in the moderate ( P = 0.07) and high ( P < 0.05) burn injury groups compared with the control group. Likewise, peak vascular conductance during postocclusive reactive hyperemia differed from the moderate burn injury group ( P = 0.08 vs. control) and the high burn injury group ( P < 0.05 vs. control). These data suggest that vasodilator function is impaired in well-healed burn injury survivors, with the extent of impairment not dependent on the magnitude of body surface area having sustained a severe burn injury.

The increase in interstitial potassium (K + ) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K + in exercise hyperemia, we perfused skeletal muscle with K + before contractions, such that the effect of any endogenously-released K + would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF) (Doppler ultrasound) and forearm vascular conductance (FVC) (FBF/mean arterial pressure) during 4 min of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions, 2) infusion of KCl before the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly before the onset of exercise (control: 39 ± 6 vs. KCl: 81 ± 12 and SNP: 82 ± 13 ml·min -1 ·100 mmHg -1 ; both P < 0.05 vs. control). Infusion of KCl at rest diminished the hyperemic (ΔFBF) and vasodilatory (ΔFVC) response to subsequent exercise by 22 ± 5% and 30 ± 5%, respectively (both P < 0.05 vs. control), whereas SNP did not affect the change in FBF ( P = 0.74 vs. control) or FVC ( P = 0.61 vs. control) from rest to steady-state exercise. These findings implicate the K + ion as an essential vasodilator substance contributing to exercise hyperemia in humans. NEW & NOTEWORTHY Our findings support a significant and obligatory role for potassium signaling in the local vasodilatory and hyperemic response to exercise in humans.

We used diffuse correlation spectroscopy to investigate sympathetic vasoconstriction, local vasodilation, and integration of these two responses in the skeletal muscle microvasculature of 20 healthy volunteers. Diffuse correlation spectroscopy probes were placed on the flexor carpi radialis muscle or vastus lateralis muscle, and a blood flow index was derived continuously. We measured hemodynamic responses during sympathoexcitation induced by forehead cooling, after which the effects of the increased sympathetic tone on vasodilatory responses during postocclusive reactive hyperemia (PORH) were examined. PORH was induced by releasing arterial occlusion (3 min) in an arm or leg. To increase sympathetic tone during PORH, forehead cooling was begun 60 s before the occlusion release and ended 60 s after the release. During forehead cooling, mean arterial pressure rose significantly and was sustained at an elevated level. Significant vasoconstriction and decreases in blood flow index followed by gradual blunting of the vasoconstriction also occurred. The time course of these responses is in good agreement with previous observations in animals. The acute sympathoexcitation diminished the peak vasodilation during PORH only in the vastus lateralis muscle, but it hastened the decline in vasodilation after the peak in both the flexor carpi radialis muscle and vastus lateralis muscle. Consequently, the total vasodilatory response assessed as the area of the vascular conductance during the first minute of PORH was significantly diminished in both regions. We conclude that, in humans, the integrated effects of sympathetic vasoconstriction and local vasodilation have an important role in vascular regulation and control of perfusion in the skeletal muscle microcirculation. NEW & NOTEWORTHY We used diffuse correlation spectroscopy to demonstrate that acute sympathoexcitation constrains local vasodilation in the human skeletal muscle microvasculature during postocclusive reactive hyperemia. This finding indicates that integration of sympathetic vasoconstriction and local vasodilation is importantly involved in vascular regulation and the control of perfusion of the skeletal muscle microcirculation in humans.

Peripheral arterial disease (PAD) is associated with augmented blood pressure (BP) and impaired coronary blood flow responses to exercise, which may increase cardiovascular risk. We investigated the effects of leg revascularization on the BP and coronary blood flow responses to exercise in PAD. Seventeen PAD patients (11 men, 66 ± 2 yr) performed single-leg plantar flexion exercise 24 h before and 1 mo following leg revascularization. BP and heart rate (HR) were measured continuously, and rate pressure product (systolic BP × HR) was calculated as an index of myocardial oxygen demand. Coronary blood velocity was obtained by transthoracic Doppler echocardiography in 8/17 subjects. The mean BP response to plantar flexion exercise was attenuated by leg revascularization (pre-revascularization: 15 ± 4 vs. post-revascularization: 7 ± 3 mmHg, P = 0.025). The HR response to plantar flexion was also attenuated following leg revascularization (pre-revascularization: 9 ± 1 vs. post-revascularization: 6 ± 1 beats/min, P = 0.006). The change in coronary blood velocity with exercise was greater at the post-revascularization visit: 4 ± 1 vs. pre-revascularization: -1 ± 2 cm/s ( P = 0.038), even though the change in rate pressure product was not greater following revascularization in these subjects (pre-revascularization: 2,796 ± 871 vs. post-revascularization: 1,766 ± 378 mmHg·beats/min, P = 0.082). These data suggest that leg revascularization alters reflex control of BP, HR, and coronary blood flow in response to exercise in patients with PAD. NEW & NOTEWORTHY We found that peripheral revascularization procedures lowered exercise blood pressure and improved coronary blood flow in patients with peripheral arterial disease.

Breathlessness during daily activities is the primary symptom in patients with heart failure (HF). Poor correlation between the hemodynamic parameters of left ventricular performance and perceived symptoms suggests that other factors, such as skeletal muscle function, play a role in determining exercise capacity. We investigated the effect of 6 wk of high-intensity, one-legged cycling (HIC; 8 × 4 at 90% one-legged cycling max) on 1) the ability to override sympathetic vasoconstriction (arterial infusion of tyramine) during one-legged knee-extensor exercise (KEE), 2) vascular function (arterial infusion of ACh, sodium nitroprusside, tyramine, and ATP), and 3) exercise capacity in HF patients with reduced ejection fraction ( n = 8) compared with healthy individuals ( n = 6). Arterial tyramine infusion lowered leg blood flow and leg vascular conductance at rest and during KEE before the training intervention in both groups ( P < 0.05) but not during KEE after the training intervention. There was no difference between groups. The peak vasodilatory response to ATP was blunted in HF patients ( P < 0.05), whereas there was no difference in ACh- and sodium nitroprusside-induced vasodilation between HF patients and healthy individuals. ACh-induced vasodilation increased in HF patients after the training intervention ( P < 0.05). HIC improved aerobic capacity in both groups ( P < 0.05), whereas only HF patients made improvements in the 6-min walking distance ( P < 0.05). These results suggest that exercise hyperemia and functional sympatholysis are not altered in HF patients and that functional sympatholysis is improved with HIC in both HF patients and healthy individuals. Moreover, these results suggest that the peak vasodilatory response to ATP is blunted in HF. NEW & NOTEWORTHY The ability to override sympathetic vasoconstrictor activity (by arterial tyramine infusion) during exercise is not different between heart failure patients and healthy individuals and is improved by high-intensity, one-legged cycling training. The peak vasodilatory response to ATP is reduced in heart failure patients.

Investigations of human conduit artery endothelial function via flow-mediated vasodilation (FMD) have largely been restricted to the reactive hyperemia (RH) technique, wherein a transient increase in shear stress after the release of limb occlusion stimulates upstream conduit artery vasodilation (RH-FMD). FMD can also be assessed in response to sustained increases in shear stress [sustained stimulus (SS)-FMD], most often created with limb heating or exercise. Exercise in particular creates a physiologically relevant stimulus because shear stress increases, and FMD occurs, during typical day-to-day activity. Several studies have identified that various conditions and acute interventions have a disparate impact on RH-FMD versus SS-FMD, sometimes with only the latter demonstrating impairment. Indeed, evidence suggests that transient (RH) and sustained (SS) shear stress stimuli may be transduced via different signaling pathways, and, as such, SS-FMD and RH-FMD appear to offer unique insights regarding endothelial function. The present review describes the techniques used to assess SS-FMD and summarizes the evidence regarding 1) SS-FMD as an index of endothelial function in humans, highlighting comparisons with RH-FMD, and 2) potential differences in shear stress transduction and vasodilator production stimulated by transient versus sustained shear stress stimuli. The evidence suggests that SS-FMD is a useful tool to assess endothelial function and that further research is required to characterize the mechanisms involved and its association with long-term cardiovascular outcomes. NEW & NOTEWORTHY Sustained increases in peripheral conduit artery shear stress, created via distal skin heating or exercise, provide a physiologically relevant stimulus for flow-mediated dilation (FMD). Sustained stimulus FMD and FMD stimulated by transient, reactive hyperemia-induced increases in shear stress provide distinct assessments of conduit artery endothelial function.

The rapid hyperemia evoked by muscle compression is short lived and was recently shown to undergo a rapid decrease even in spite of continuing mechanical stimulation. The present study aims at investigating the mechanisms underlying this attenuation, which include local metabolic mechanisms, desensitization of mechanosensitive pathways, and reduced efficacy of the muscle pump. In 10 healthy subjects, short sequences of mechanical compressions ( n = 3-6; 150 mmHg) of the lower leg were delivered at different interstimulus intervals (ranging from 20 to 160 s) through a customized pneumatic device. Hemodynamic monitoring included near-infrared spectroscopy, detecting tissue oxygenation and blood volume in calf muscles, and simultaneous echo-Doppler measurement of arterial (superficial femoral artery) and venous (femoral vein) blood flow. The results indicate that 1 ) a long-lasting (>100 s) increase in local tissue oxygenation follows compression-induced hyperemia, 2 ) compression-induced hyperemia exhibits different patterns of attenuation depending on the interstimulus interval, 3 ) the amplitude of the hyperemia is not correlated with the amount of blood volume displaced by the compression, and 4 ) the extent of attenuation negatively correlates with tissue oxygenation ( r  = -0,78, P < 0.05). Increased tissue oxygenation appears to be the key factor for the attenuation of hyperemia upon repetitive compressive stimulation. Tissue oxygenation monitoring is suggested as a useful integration in medical treatments aimed at improving local circulation by repetitive tissue compression. NEW & NOTEWORTHY This study shows that 1 ) the hyperemia induced by muscle compression produces a long-lasting increase in tissue oxygenation, 2 ) the hyperemia produced by subsequent muscle compressions exhibits different patterns of attenuation at different interstimulus intervals, and 3 ) the extent of attenuation of the compression-induced hyperemia is proportional to the level of oxygenation achieved in the tissue. The results support the concept that tissue oxygenation is a key variable in blood flow regulation., (Copyright © 2017 the American Physiological Society.)

Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy ( P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy ( P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy ( P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy ( P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy., (Copyright © 2017 the American Physiological Society.)

Spreading depolarization (SD) events contribute to lesion maturation in the acutely injured human brain. Neurodegeneration related to SD is thought to be caused by the insufficiency of the cerebral blood flow (CBF) response; yet the mediators of the CBF response, or their deficiency in the aged or ischemic cerebral cortex, remain the target of intensive research. Here, we postulated that tissue pH effectively modulates the magnitude of hyperemia in response to SD, the coupling of which is prone to be dysfunctional in the aged or ischemic cerebral cortex. To test this hypothesis, we conducted systematic correlation analysis between the direct current (DC) potential signature of SD, SD-associated tissue acidosis, and hyperemic element of the CBF response in the isoflurane-anesthetized, young or old, and intact or ischemic rat cerebral cortex. The data demonstrate that the amplitude of the SD-related DC potential shift, tissue acidosis, and hyperemia are tightly coupled in the young intact cortex; ischemia and old age uncouples the amplitude of hyperemia from the amplitude of the DC potential shift and acidosis; the duration of the DC potential shift, hyperemia and acidosis positively correlate under ischemia alone; and old age disproportionally elongates the duration of acidosis with respect to the DC potential shift and hyperemia under ischemia. The coincidence of the variables supports the view that local CBF regulation with SD must have an effective metabolic component, which becomes dysfunctional with age or under ischemia. Finally, the known age-related acceleration of ischemic neurodegeneration may be promoted by exaggerated tissue acidosis. NEW & NOTEWORTHY The hyperemic element of the cerebral blood flow response to spreading depolarization is effectively modulated by tissue pH in the young intact rat cerebral cortex. This coupling becomes dysfunctional with age or under ischemia, and tissue acidosis lasts disproportionally longer in the aged cortex, making the tissue increasingly more vulnerable., (Copyright © 2017 the American Physiological Society.)

During exercise, β-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of β-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that β1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective β-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t -tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; P = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective β1 blockade reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia. NEW & NOTEWORTHY In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary β1 and β2 adrenergic receptors in humans., (Copyright © 2017 the American Physiological Society.)

The present study sought to compare the temporal relation between maximal coronary flow (peak hyperemia) and minimal coronary-to-aortic pressure ratio (P d /P a ) for intracoronary (IC) and intravenous (IV) adenosine administration. Peak hyperemia is assumed to coincide with the minimal P d /P a value. However, this has not been confirmed for systemic hemodynamic variations during IV adenosine infusion. Hemodynamic responses to IV and IC adenosine administration were obtained in 12 patients (14 lesions) using combined IC pressure and flow velocity measurements. A fluid dynamic model was used to predict the change in P d /P a for different stenosis severities and varying P a Hemodynamic variability during IV adenosine hyperemia was greater than during IC adenosine, as assessed by the coefficient of variation. During IV adenosine, flow velocity peaked 28 ± 4 (SE) s after the onset of hyperemia, while P d /P a reached a minimum (0.82 ± 0.01) 22 ± 7 s later ( P < 0.05), when P a had declined by 6.1% and hyperemic velocity by 4.5% ( P < 0.01). Model outcomes corroborated the role of variable P a in this dissociation. In contrast, maximal flow and minimal P d /P a coincided for IC adenosine, with IV-equivalent peak velocities and a higher P d /P a ratio (0.86 ± 0.01, P < 0.01). Hemodynamic variability during continuous IV adenosine infusion can lead to temporal dissociation of minimal P d /P a and peak hyperemia, in contrast to IC adenosine injection, where maximal velocity and minimal P d /P a coincide. Despite this variability, stenosis hemodynamics remained stable with both ways of adenosine administration. Our findings suggest advantages of IC over IV adenosine to identify maximal hyperemia from pressure-only measurements. NEW & NOTEWORTHY Systemic hemodynamic variability during intravenous adenosine infusion produces substantial temporal dissociation between peak hyperemia appraised by coronary flow velocity and the minimal distal-to-aortic pressure ratio commonly used to determine functional stenosis severity. This dissociation was absent for intracoronary adenosine administration and tended to be mitigated in patients receiving Ca 2+ antagonists., (Copyright © 2017 the American Physiological Society.)

Neurovascular coupling (NVC) describes the link between an increase in task-related neural activity and increased cerebral blood flow denoted "functional hyperemia." We previously showed induced cerebral blood flow oscillations suppressed functional hyperemia; conversely functional hyperemia also suppressed cerebral blood flow oscillations. We used lower body negative pressure (OLBNP) oscillations to force oscillations in middle cerebral artery cerebral blood flow velocity (CBFv). Here, we used N-back testing, an intellectual memory challenge as a neural activation task, to test the hypothesis that OLBNP-induced oscillatory cerebral blood flow can reduce functional hyperemia and NVC produced by a working memory task and can interfere with working memory. We used OLBNP (-30 mmHg) at 0.03, 0.05, and 0.10 Hz and measured spectral power of CBFv at all frequencies. Neither OLBNP nor N-back, alone or combined, affected hemodynamic parameters. 2-Back power and OLBNP individually were compared with 2-back power during OLBNP. 2-Back alone produced a narrow band increase in oscillatory arterial pressure (OAP) and oscillatory cerebral blood flow power centered at 0.0083 Hz. Functional hyperemia in response to 2-back was reduced to near baseline and 2-back memory performance was decreased by 0.03-, 0.05-, and 0.10-Hz OLBNP. OLBNP alone produced increased oscillatory power at frequencies of oscillation not suppressed by added 2-back. However, 2-back preceding OLBNP suppressed OLBNP power. OLBNP-driven oscillatory CBFv blunts NVC and memory performance, while memory task reciprocally interfered with forced CBFv oscillations. This shows that induced cerebral blood flow oscillations suppress functional hyperemia and functional hyperemia suppresses cerebral blood flow oscillations. NEW & NOTEWORTHY We show that induced cerebral blood flow oscillations suppress functional hyperemia produced by a working memory task as well as memory task performance. We conclude that oscillatory cerebral blood flow produces causal reductions of memory task neurovascular coupling and memory task performance. Reductions of functional hyperemia are constrained by autoregulation., (Copyright © 2017 the American Physiological Society.)

African Americans (AA) exhibit exaggerated central blood pressure (BP) and arterial stiffness measured by pulse wave velocity (PWV) in response to an acute bout of maximal exercise compared with Caucasians (CA). However, whether potential racial differences exist in central BP, elastic, or muscular arterial distensibility after submaximal aerobic exercise remains unknown. Histamine receptor activation mediates sustained postexercise hyperemia in CA but the effect on arterial stiffness is unknown. This study sought to determine the effects of an acute bout of aerobic exercise on central BP and arterial stiffness and the role of histamine receptors, in AA and CA. Forty-nine (22 AA, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either histamine receptor antagonist or control placebo. Central blood BP and arterial stiffness measurements were obtained at baseline, and at 30, 60, and 90 min after 45 min of moderate treadmill exercise. AA exhibited greater central diastolic BP, elevated brachial PWV, and local carotid arterial stiffness after an acute bout of submaximal exercise compared with CA, which may contribute to their higher risk of cardiovascular disease. Unexpectedly, histamine receptor blockade did not affect central BP or PWV in AA or CA after exercise, but it may play a role in mediating local carotid arterial stiffness. Furthermore, histamine may mediate postexercise carotid arterial dilation in CA but not in AA. These observations provide evidence that young and healthy AA exhibit an exaggerated hemodynamic response to exercise and attenuated vasodilator response compared with CA. NEW & NOTEWORTHY African Americans are at greater risk for developing cardiovascular disease than Caucasians. We are the first to show that young and healthy African Americans exhibit greater central blood pressure, elevated brachial stiffness, and local carotid arterial stiffness following an acute bout of submaximal exercise compared with Caucasians, which may contribute to their higher risk of cardiovascular disease. Furthermore, African Americans exhibit attenuated vasodilator response compared with Caucasians., (Copyright © 2017 the American Physiological Society.)

Local heating of an extremity increases blood flow and vascular shear stress throughout the arterial tree. Local heating acutely improves macrovascular dilator function in the upper limbs of young healthy adults through a shear stress-dependent mechanism but has no such effect in the lower limbs of this age group. The effect of acute limb heating on dilator function within the atherosclerotic prone vasculature of the lower limbs of aged adults is unknown. Therefore, the purpose of this study was to test the hypothesis that acute lower limb heating improves macro- and microvascular dilator function within the leg vasculature of aged adults. Nine young and nine aged adults immersed their lower limbs at a depth of ~33 cm into a heated (~42°C) circulated water bath for 45 min. Before and 30 min after heating, macro (flow-mediated dilation)- and microvascular (reactive hyperemia) dilator functions were assessed in the lower limb, following 5 min of arterial occlusion, via Doppler ultrasound. Compared with preheat, macrovascular dilator function was unchanged following heating in young adults (P = 0.6) but was improved in aged adults (P = 0.04). Similarly, microvascular dilator function, as assessed by peak reactive hyperemia, was unchanged following heating in young adults (P = 0.1) but was improved in aged adults (P < 0.01). Taken together, these data suggest that acute lower limb heating improves both macro- and microvascular dilator function in an age dependent manner., New & Noteworthy: We demonstrate that lower limb heating acutely improves macro- and microvascular dilator function within the atherosclerotic prone vasculature of the leg in aged adults. These findings provide evidence for a potential therapeutic use of chronic lower limb heating to improve vascular health in primary aging and various disease conditions., (Copyright © 2017 the American Physiological Society.)

Passive leg movement (PLM)-induced hyperemia is a novel approach to assess vascular function, with a potential clinical role. However, in some instances, the varying chronotropic response induced by PLM has been proposed to be a potentially confounding factor. Therefore, we simplified and modified the PLM model to require just a single PLM (sPLM), an approach that may evoke a peripheral hemodynamic response, allowing a vascular function assessment, but at the same time minimizing central responses. To both characterize and assess the utility of sPLM, in 12 healthy subjects, we measured heart rate (HR), stroke volume, cardiac output (CO), mean arterial pressure (MAP), leg blood flow (LBF), and calculated leg vascular conductance (LVC) during both standard PLM, consisting of passive knee flexion and extension performed at 1 Hz for 60 s, and sPLM, consisting of only a single passive knee flexion and extension over 1 s. During PLM, MAP transiently decreased (5 ± 1 mmHg), whereas both HR and CO increased from baseline (6.0 ± 1.1 beats/min, and 0.8 ± 0.01 l/min, respectively). Following sPLM, MAP fell similarly (5 ± 2 mmHg; P = 0.8), but neither HR nor CO responses were identifiable. The peak LBF and LVC response was similar for PLM (993 ± 189 ml/min; 11.9 ± 1.5 ml·min -1 ·mmHg -1 , respectively) and sPLM (878 ± 119 ml/min; 10.9 ± 1.6 ml·min -1 ·mmHg -1 , respectively). Thus sPLM represents a variant of the PLM approach to assess vascular function that is more easily performed and evokes a peripheral stimulus that induces a significant hyperemia, but does not generate a potentially confounding, chronotropic response, which may make sPLM more useful clinically., New & Noteworthy: Using the single passive leg movement (PLM) technique, a variant of the vascular function assessment PLM, we have identified a novel peripheral vascular assessment method that is more easily performed than PLM, which, by not evoking potentially confounding central hemodynamic responses, may be more useful clinically.

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by debilitating fibrosis and vascular dysfunction; however, little is known about the circulatory response to exercise in this population. Therefore, we examined the peripheral hemodynamic and vasodilatory responses to handgrip exercise in 10 patients with SSc (61 ± 4 yr) and 15 age-matched healthy controls (56 ± 5 yr). Brachial artery diameter, blood flow, and mean arterial pressure (MAP) were determined at rest and during progressive static-intermittent handgrip exercise. Patients with SSc and controls were similar in body stature, handgrip strength, and MAP; however, brachial artery blood flow at rest was nearly twofold lower in patients with SSc compared with controls (22 ± 4 vs. 42 ± 5 ml/min, respectively; P < 0.05). Additionally, SSc patients had an ∼18% smaller brachial artery lumen diameter with an ∼28% thicker arterial wall at rest (P < 0.05). Although, during handgrip exercise, there were no differences in MAP between the groups, exercise-induced hyperemia and therefore vascular conductance were ∼35% lower at all exercise workloads in patients with SSc (P < 0.05). Brachial artery vasodilation, as assessed by the relationship between Δbrachial artery diameter and Δshear rate, was significantly attenuated in the patients with SSc (P < 0.05). Finally, vascular dysfunction in the patients with SSc was accompanied by elevated blood markers of oxidative stress and attenuated endogenous antioxidant activity (P < 0.05). Together, these findings reveal attenuated exercise-induced brachial artery blood flow and conduit arterial vasodilatory dysfunction during handgrip exercise in SSc and suggest that elevated oxidative stress may play a role.

Intermittent hypoxia (IH) occurs in association with obstructive sleep apnea and likely contributes to the pathogenesis of hypertension. The purpose of this study was to examine the putative early adaptations at the level of the peripheral vasculature and carotid baroreflex (CBR) that may promote the development of hypertension. Ten healthy male participants (26 ± 1 yr, BMI = 24 ± 1 kg/m(2)) were exposed to 6 h of IH (1-min cycles of normoxia and hypoxia) and SHAM in a single-blinded, counterbalanced crossover study design. Ambulatory blood pressure was measured during each condition and the following night. Vascular strain of the carotid and femoral artery, a measure of localized arterial stiffness, and hemodynamic shear patterns in the brachial and femoral arteries were measured during each condition. Brachial artery reactive hyperemia flow-mediated vasodilation was assessed before and after each condition as a measure of endothelial function. CBR function and its control over leg vascular conductance (LVC) were measured after each condition with a variable-pressure neck chamber. Intermittent hypoxia 1) increased nighttime pulse pressure by 3.2 ± 1.3 mmHg, 2) altered femoral but not brachial artery hemodynamics, 3) did not affect brachial artery endothelial function, 4) reduced vascular strain in the carotid and possibly femoral artery, and 5) shifted CBR mean arterial pressure (MAP) to higher MAP while blunting LVC responses to CBR loading. These results suggest limb-specific vascular impairments, reduced vascular strain, and CBR resetting combined with blunted LVC responses are factors in the early pathogenesis of IH-induced development of hypertension., (Copyright © 2016 the American Physiological Society.)

This study investigates whether hyperemic microvascular resistance (MR) is influenced by elective percutaneous coronary intervention (PCI) by using the index of microcirculatory resistance (IMR). Seventy-one consecutive patients with stable angina pectoris undergoing elective PCI were prospectively studied. The IMR was measured before and after PCI and at the 10-mo follow-up. The IMR significantly decreased until follow-up; the pre-PCI, post-PCI, and follow-up IMRs had a median of 19.8 (interquartile range, 14.6-28.9), 16.2 (11.8-22.1), and 14.8 (11.8-18.7), respectively (P < 0.001). The pre-PCI IMR was significantly correlated with the change in IMR between pre- and post-PCI (r = 0.84, P < 0.001) and between pre-PCI and follow-up (r = 0.93, P < 0.001). Pre-PCI IMR values were significantly higher in territories with decreases in IMR than in those with increases in IMR [pre-PCI IMR: 25.4 (18.4-35.5) vs. 12.5 (9.4-16.8), P < 0.001]. At follow-up, IMR values in territories showing decreases in IMR were significantly lower than those with increases in IMR [IMR at follow-up: 13.9 (10.9-17.6) vs. 16.6 (14.0-21.4), P = 0.013]. The IMR decrease was significantly associated with a greater shortening of mean transit time, indicating increases in coronary flow (P < 0.001). The optimal cut-off values of pre-PCI IMR to predict a decrease in IMR after PCI and at follow-up were 16.8 and 17.0, respectively. In conclusion, elective PCI affected hyperemic MR and its change was associated with pre-PCI MR, resulting in showing a wide distribution. Overall hyperemic MR significantly decreased until follow-up. The modified hyperemic MR introduced by PCI may affect post-PCI coronary flow., (Copyright © 2016 the American Physiological Society.)

In humans, intra-arterial ATP infusion in limbs mimics many features of exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore, we addressed two questions during a continuous 3-h brachial artery infusion of ATP [20 μg·100 ml forearm volume (FAV)(-1)·min(-1)]: 1) would skeletal muscle blood flow remain robust or wane over time (tachyphylaxis); and 2) would the hyperemic response to moderate-intensity exercise performed during the ATP administration be blunted compared with that during control (saline) infusion. Nine participants (25 ± 1 yr) performed one trial consisting of seven bouts of rhythmic handgrip exercise (20 contractions/min at 20% of maximum), two bouts during saline (control), and five bouts during 180 min of continuous ATP infusion. Five minutes of ATP infusion resulted in a 710% increase in forearm vascular conductance (FVC) from control (4.8 ± 0.77 vs. 35.0 ± 5.7 ml·min(-1)·100 mmHg(-1)·dl FAV(-1), P < 0.05). Contrary to our expectations, FVC did not wane over time with values of 35.0 ± 5.7 and 36.0 ± 7.7 ml·min(-1)·100 mmHg(-1)·dl FAV(-1) (P > 0.05), seen prior to the exercise bouts at 5 vs. 150 min, respectively. During superimposed exercise, FVC increased from 35.0 ± 5.7 to 49.6 ± 5.4 ml·min(-1)·100 mmHg(-1)·dl FAV(-1) at 5 min and 36.0 ± 7.7 to 54.5 ± 5.0 at 150 min (P < 0.05). Our findings demonstrate ATP vasodilation is prolonged over time without tachyphylaxis; however, exercise hyperemia responses remain intact. Our results challenge the metabolic theory of exercise hyperemia, suggesting a disconnect between matching of blood flow and metabolic demand., (Copyright © 2016 the American Physiological Society.)

Sympathetic neural activation may be detrimentally involved in tissue injury caused by ischemia-reperfusion (IR). We examined the effects of experimental IR in the forearm on sympathetic nerve response, finger reactive hyperemia, and oxidative stress, and the protection afforded by applying remote ischemic preconditioning (RIPC). Ischemia was induced in the forearm for 20 min in healthy volunteers. RIPC was induced by applying two cycles, 5 min each, of ischemia and reperfusion to the upper leg immediately before IR. We examined muscle sympathetic nerve activity (MSNA) in the contralateral leg using microneurography, finger reactive hyperemia [ischemic reactive hyperemia index (RHI)], erythrocyte production of reduced gluthathione (GSH), and plasma nitric oxide (NO) concentration. In controls (no RIPC; n = 15), IR increased MSNA in the early and late phase of ischemia (70% at 5 min; 101% at 15 min). In subjects who underwent RIPC (n = 15), the increase in MSNA was delayed to the late phase of ischemia and increased only by 40%. GSH increased during ischemia in the control group (P = 0.05), but not in those who underwent RIPC. Nitrate and nitrite concentration, taken as an index of NO availability, decreased during the reperfusion period in control individuals (P < 0.05), while no change was observed in those who underwent RIPC. Experimental IR did not affect RHI in the control condition, but a significant vasodilatory response occurred in the RIPC group (P < 0.05). RIPC attenuated ischemia-induced sympathetic activation, prevented the production of an erythrocyte marker of oxidative stress and the reduction of NO availability, and ameliorated RHI., (Copyright © 2016 the American Physiological Society.)

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes., (Copyright © 2016 the American Physiological Society.)

Prolonged sitting impairs endothelial function in the leg vasculature, and this impairment is thought to be largely mediated by a sustained reduction in blood flow-induced shear stress. Indeed, preventing the marked reduction of shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Herein, we tested the hypothesis that sitting-induced reductions in shear stress and ensuing endothelial dysfunction would be prevented by periodic leg movement, or "fidgeting." In 11 young, healthy subjects, bilateral measurements of popliteal artery flow-mediated dilation (FMD) were performed before and after a 3-h sitting period during which one leg was subjected to intermittent fidgeting (1 min on/4 min off) while the contralateral leg remained still throughout and served as an internal control. Fidgeting produced a pronounced increase in popliteal artery blood flow and shear rate (prefidgeting, 33.7 ± 2.6 s(-1) to immediately postfidgeting, 222.7 ± 28.3 s(-1); mean ± SE; P < 0.001) that tapered off during the following 60 s. Fidgeting did not alter popliteal artery blood flow and shear rate of the contralateral leg, which was subjected to a reduction in blood flow and shear rate throughout the sitting period (presit, 71.7 ± 8.0 s(-1) to 3-h sit, 20.2 ± 2.9 s(-1); P < 0.001). Popliteal artery FMD was impaired after 3 h of sitting in the control leg (presit, 4.5 ± 0.3% to postsit: 1.6 ± 1.1%; P = 0.039) but improved in the fidgeting leg (presit, 3.7 ± 0.6% to postsit, 6.6 ± 1.2%; P = 0.014). Collectively, the present study provides evidence that prolonged sitting-induced leg endothelial dysfunction is preventable with small amounts of leg movement while sitting, likely through the intermittent increases in vascular shear stress., (Copyright © 2016 the American Physiological Society.)

Cystic fibrosis (CF) is a genetic, multisystemic disorder with broad clinical manifestations apart from the well-characterized pulmonary dysfunction. Recent findings have described impairment in conduit vessel function in patients with CF; however, whether microvascular function is affected in this population has yet to be elucidated. Using laser-Doppler imaging, we evaluated microvascular function through postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh). PORH [518 ± 174% (CF) and 801 ± 125% (control), P = 0.039], LTH [1,338 ± 436% (CF) and 1,574 ± 620% (control), P = 0.045], and iontophoresis with ACh [416 ± 140% (CF) and 617 ± 143% (control), P = 0.032] were significantly lower in patients with CF than control subjects. In addition, the ratio of PORH to LTH was significantly (P = 0.043) lower in patients with CF (55.3 ± 5.1%) than control subjects (68.8 ± 3.1%). Significant positive correlations between LTH and forced expiratory volume in 1 s (%predicted) (r = 0.441, P = 0.013) and between the PORH-to-LTH ratio and exercise capacity (r = 0.350, P = 0.049) were observed. These data provide evidence of microvascular dysfunction in patients with CF compared with control subjects. In addition, our data demonstrate a complex relationship between microvascular function and classical markers of disease severity (i.e., pulmonary function and exercise capacity) in CF., (Copyright © 2016 the American Physiological Society.)

Post-cuff occlusion flow-mediated dilation (FMD) is a proposed indicator of nitric oxide (NO) bioavailability and vascular function. FMD is reduced in patients with sepsis and may be a marker of end organ damage and mortality. However, FMD likely does not solely reflect NO-mediated vasodilation, is technically challenging, and often demonstrates poor reproducibility. In contrast, passive leg movement (PLM), a novel methodology to assess vascular function, yields a hyperemic response that is predominately NO-dependent, reproducible, and easily measured. This study evaluated PLM as an approach to assess NO-mediated vascular function in patients with sepsis. We hypothesized that PLM-induced hyperemia, quantified by the increase in leg blood flow (LBF), would be attenuated in sepsis. In a cross-sectional study, 17 subjects in severe sepsis or septic shock were compared with 16 matched healthy controls. Doppler ultrasound was used to assess brachial artery FMD and the hyperemic response to PLM in the femoral artery. FMD was attenuated in septic compared with control subjects (1.1 ± 1.7% vs. 6.8 ± 1.3%; values are means ± SD). In terms of PLM, baseline LBF (196 ± 33 ml/min vs. 328 ± 20 ml/min), peak change in LBF from baseline (133 ± 28 ml/min vs. 483 ± 86 ml/min), and the LBF area under the curve (16 ± 8.3 vs. 143 ± 33) were all significantly attenuated in septic subjects. Vascular function, as assessed by both FMD and PLM, is attenuated in septic subjects compared with controls. These data support the concept that NO bioavailability is attenuated in septic subjects, and PLM appears to be a novel and feasible approach to assess NO-mediated vascular function in sepsis.

Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2 ); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end-tidal Po2(PetO2 ) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (V̇e) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While V̇ewas uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, V̇ewas increased to prevent PetCO2 from rising above resting values (∼40 mmHg). Although PetCO2 differed by 2 ± 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (∼12-15%) and extracranial (15-20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (∼17-29%) were greater compared with poikilocapnic normoxia (∼8-20%) at intensities >40% Wmax(P< 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2., (Copyright © 2016 the American Physiological Society.)

Computational predictions of the functional stenosis severity from coronary imaging data use an allometric scaling law to derive hyperemic blood flow (Q) from coronary arterial volume (V), Q = αV(β) Reliable estimates of α and β are essential for meaningful flow estimations. We hypothesize that the relation between Q and V depends on imaging resolution. In five canine hearts, fluorescent microspheres were injected into the left anterior descending coronary artery during maximal hyperemia. The coronary arteries of the excised heart were filled with fluorescent cast material, frozen, and processed with an imaging cryomicrotome to yield a three-dimensional representation of the coronary arterial network. The effect of limited image resolution was simulated by assessing scaling law parameters from the virtual arterial network at 11 truncation levels ranging from 50 to 1,000 μm segment radius. Mapped microsphere locations were used to derive the corresponding relative Q using a reference truncation level of 200 μm. The scaling law factor α did not change with truncation level, despite considerable intersubject variability. In contrast, the scaling law exponent β decreased from 0.79 to 0.55 with increasing truncation radius and was significantly lower for truncation radii above 500 μm vs. 50 μm (P< 0.05). Hyperemic Q was underestimated for vessel truncation above the reference level. In conclusion, flow-crown volume relations confirmed overall power law behavior; however, this relation depends on the terminal vessel radius that can be visualized. The scaling law exponent β should therefore be adapted to the resolution of the imaging modality., (Copyright © 2016 the American Physiological Society.)

Neurovascular coupling refers to the link between an increase in neural activity in response to a task and an increase in cerebral blood flow denoted "functional hyperemia." Recent work on postural tachycardia syndrome indicated that increased oscillatory cerebral blood flow velocity (CBFv) was associated with reduced functional hyperemia. We hypothesized that a reduction in functional hyperemia could be causally produced in healthy volunteers by using oscillations in lower body negative pressure (OLBNP) to force oscillations in CBFv. CBFv was measured by transcranial Doppler ultrasound of the left middle cerebral artery. We used passive arm flexion applied during eight periodic 60-s flexion/60-s relaxation epochs to produce 120-s periodic changes in functional hyperemia (at 0.0083 Hz). We used -30 mmHg of OLBNP at 0.03, 0.05, and 0.10 Hz, the range for cerebral autoregulation, and measured spectral power of CBFv at all frequencies. Arm flexion power performed without OLBNP was compared with arm flexion power during OLBNP. OLBNP power performed in isolation was compared with power during OLBNP plus arm flexion. Cerebral flow velocity oscillations at 0.05 Hz reduced and at 0.10 Hz eliminated functional hyperemia, while 0.03 Hz did not reach significance. In contrast, arm flexion reduced OLBNP-induced oscillatory power at all frequencies. The interactions between OLBNP-driven CBFv oscillations and arm flexion-driven CBFv oscillations are reciprocal. Thus induced cerebral blood flow oscillations suppress functional hyperemia, and functional hyperemia suppresses cerebral blood flow oscillations. We conclude that oscillatory cerebral blood flow produces a causal reduction of functional hyperemia., (Copyright © 2016 the American Physiological Society.)

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS(-/-)) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS(-/-) mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia., (Copyright © 2015 the American Physiological Society.)