Preserved endothelium-independent vascular function with aging in men and women: evidence from the peripheral and cerebral vasculature.

In the peripheral and cerebral vasculature, the impact of aging and sex on the endothelial-independent functional capacity of vascular smooth muscle cells (VSMCs) is not well understood, nor is it known whether such VSMC functions in these vascular beds reflect one another. Therefore, endothelium-independent dilation, at both the conduit (Δ diameter) and microvascular (Δ vascular conductance, VC) level, elicited by sublingual nitroglycerin (NTG, 0.8 mg of Nitrostat), compared with sham-delivery (control), was assessed using Doppler ultrasound in the popliteal (PA) and middle cerebral (MCA) artery of 20 young [23 ± 4 yr, 10 males (YM)/10 females (YF)] and 21 old [69 ± 5 yr, 11 males (OM)/10 females (OF)] relatively healthy adults. In the PA, compared with zero, NTG significantly increased diameter in all groups (YM: 0.29 ± 0.13, YF: 0.35 ± 0.26, OM: 0.30 ± 0.18, OF: 0.31 ± 0.14 mm), while control did not. The increase in VC only achieved significance in the OF (0.22 ± 0.31 mL/min/mmHg). In the MCA, compared with zero, NTG significantly increased diameter and VC in all groups (YM: 0.89 ± 0.30, 1.06 ± 1.28; YF: 0.97 ± 0.31, 1.84 ± 1.07; OM: 0.90 ± 0.42, 0.72 ± 0.99; OF: 0.74 ± 0.32, 1.19 ± 1.18, mm and mL/min/mmHg, respectively), while control did not. There were no age or sex differences or age-by-sex interactions for both the NTG-induced PA and MCA dilation and VC. In addition, PA and MCA dilation and VC responses to NTG were not related when grouped by age, sex, or as all subjects (r = 0.04-0.44, P > 0.05). Thus, peripheral and cerebral endothelial-independent VSMC function appears to be unaffected by age or sex, and variations in such VSMC function in one of these vascular beds are not reflected in the other.NEW & NOTEWORTHY To confidently explain peripheral and cerebral vascular dysfunction, it is essential to have a clear understanding of the endothelial-independent function of VSMCs across age and sex. By assessing endothelium-independent dilation using sublingual nitroglycerin, endothelial-independent VSMC function in the periphery (popliteal artery), and in the cerebral circulation (middle cerebral artery), was not different due to age or sex. In addition, endothelial-independent VSMC function in one of these vascular beds is not reflected in the other.

Pharmacological modulation of adrenergic tone alters the vasodilatory response to passive leg movement in young but not in old adults.

The age-related increase in α-adrenergic tone may contribute to decreased leg vascular conductance (LVC) both at rest and during exercise in the old. However, the effect on passive leg movement (PLM)-induced LVC, a measure of vascular function, which is markedly attenuated in this population, is unknown. Thus, in eight young (25 ± 5 yr) and seven old (65 ± 7 yr) subjects, this investigation examined the impact of systemic ß-adrenergic blockade (propanalol, PROP) alone, and PROP combined with either α1-adrenergic stimulation (phenylephrine, PE) or α-adrenergic inhibition (phentolamine, PHEN), on PLM-induced vasodilation. LVC, calculated from femoral artery blood flow and pressure, was determined and PLM-induced Δ peak (LVCΔpeak) and total vasodilation (LVCAUC, area under curve) were documented. PROP decreased LVCΔpeak (PROP: 4.8 ± 1.8, Saline: 7.7 ± 2.7 mL·mmHg-1, P < 0.001) and LVCAUC (PROP: 1.1 ± 0.7, Saline: 2.4 ± 1.6 mL·mmHg-1, P = 0.002) in the young, but not in the old (LVCΔpeak, P = 0.931; LVCAUC, P = 0.999). PE reduced baseline LVC (PE: 1.6 ± 0.4, PROP: 2.3 ± 0.4 mL·min-1·mmHg-1, P < 0.01), LVCΔpeak (PE: 3.2 ± 1.3, PROP: 4.8 ± 1.8 mL·min-1·mmHg-1, P = 0.004), and LVCAUC (PE: 0.5 ± 0.4, PROP: 1.1 ± 0.7 mL·mmHg-1, P = 0.011) in the young, but not in the old (baseline LVC, P = 0.199; LVCΔpeak, P = 0.904; LVCAUC, P = 0.823). PHEN increased LVC at rest and throughout PLM in both groups (drug effect: P < 0.05), however LVCΔpeak was only improved in the young (PHEN: 6.4 ± 3.1, PROP: 4.4 ± 1.5 mL·min-1·mmHg-1, P = 0.004), and not in the old (P = 0.904). Furthermore, the magnitude of α-adrenergic modulation (PHEN - PE) of LVCΔpeak was greater in the young compared with the old (Young: 3.35 ± 2.32, Old: 0.40 ± 1.59 mL·min-1·mmHg-1, P = 0.019). Therefore, elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.NEW & NOTEWORTHY Stimulation of α1-adrenergic receptors eliminated age-related differences in passive leg movement (PLM) by decreasing PLM-induced vasodilation in the young. Systemic ß-blockade attenuated the central hemodynamic component of the PLM response in young individuals. Inhibition of α-adrenergic receptors did not improve the PLM response in older individuals, though withdrawal of α-adrenergic modulation augmented baseline and maximal vasodilation in both groups. Accordingly, α-adrenergic signaling plays a role in modulating the PLM vasodilatory response in young but not in old adults, and elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.

Reliability of the passive leg movement assessment of vascular function in men.

NEW FINDINGS: What is the central question of this study? Use of the passive leg movement (PLM) test, a non-invasive assessment of microvascular function, is on the rise. However, PLM reliability in men has not been adequately investigated, nor has such reliability data, in men, been compared to the most commonly employed vascular function assessment, flow-mediated vasodilation (FMD). What is the main finding and its importance? PLM is a reliable method to assess vascular function in men, and is comparable to values previously reported for PLM in women, and for FMD. Given the importance of vascular function as a predictor of cardiovascular disease risk, these data support the utility of PLM as a clinically relevant measurement. ABSTRACT: Although vascular function is an independent predictor of cardiovascular disease risk, and therefore has significant prognostic value, there is currently not a single clinically accepted method of assessment. The passive leg movement (PLM) assessment predominantly reflects microvascular endothelium-dependent vasodilation and can identify decrements in vascular function with advancing age and pathology. Reliability of the PLM model was only recently determined in women, and has not been adequately investigated in men. Twenty healthy men (age: 27 ± 2 year) were studied on three separate experimental days, resulting in three within-day and three between-day trials. The hyperemic response to PLM was assessed with Doppler ultrasound, and expressed as the absolute peak in leg blood flow (LBFpeak ), change from baseline to peak (ΔLBFpeak ), absolute area under the curve (LBFAUC ), and change in AUC from baseline (ΔLBFAUC ). PLM-induced hyperemia yielded within-day coefficients of variation (CV) from 10.9 to 22.9%, intraclass correlation coefficients (ICC) from 0.82 to 0.90, standard error of the measurement (SEM) from 8.3 to 17.2%, and Pearson's correlation coefficients (r) from 0.56 to 0.81. Between-day assessments of PLM hyperemia resulted in CV from 14.4 to 25%, ICC from 0.75 to 0.87, SEM from 9.8 to 19.8%, and r from 0.46 to 0.75. Similar to previous reports in women, the hyperemic responses to PLM in men display moderate-to-high reliability, and are comparable to reliability data for brachial artery flow mediated vasodilation. These positive reliability findings further support the utility of PLM as a clinical measurement of vascular function and cardiovascular disease risk.

Postexercise Hypotension Is Delayed in Men With Obesity and Hypertension.

Background: Postexercise hypotension (PEH) can play a major role in the daily blood pressure management among individuals with hypertension. However, there are limited data on PEH in persons with obesity and hypertension, and no PEH data in this population beyond 90 min postexercise. Purpose: The purpose of this study was to determine if PEH could be elicited in men with obesity and hypertension during a 4-h postexercise measurement period. Methods: Seven men [age = 28 ± 4 years; body mass index = 34.6 ± 4.8 kg/m2; brachial systolic blood pressure (SBP): 138 ± 4 mmHg; brachial diastolic BP (DBP): 80 ± 5 mmHg; central SBP: 125 ± 4 mmHg; central DBP: 81 ± 8 mmHg] performed two exercise sessions on a cycle ergometer, each on a separate day, for 45 min at ∼65% VO2max. One exercise session was performed at a cadence of 45 RPM and one at 90 RPM. Blood pressure was monitored with a SunTech Oscar2 ambulatory blood pressure monitor for 4 h after both exercise sessions, and during a time-matched control condition. Results: Both brachial and central SBP were not changed during the first h postexercise but were reduced by ∼5-11 mmHg between 2 and 4 h postexercise (p < 0.05) after both exercise sessions. Brachial and central DBP were elevated by ∼5 mmHg at 1 h postexercise (p < 0.05) but were ∼2-3 mmHg lower compared to control at 4 h postexercise, and ∼2-4 mmHg lower at 3 h postexercise compared to baseline. Mean arterial pressure (MAP) was elevated compared to control at 1 h postexercise after both exercise sessions, but was ∼2-3 mmHg lower compared to control at 2, 3, and 4 h postexercise, and ∼4-7 mmHg lower at 3 h postexercise compared to baseline. Conclusion: Despite the small sample size and preliminary nature of our results, we conclude that PEH is delayed in men with obesity and hypertension, but the magnitude and duration of PEH up to 4 h postexercise is similar to that reported in the literature for men without obesity and hypertension. The PEH is most pronounced for brachial and central SBP and MAP. The virtually identical pattern of PEH after both exercise trials indicates that the delayed PEH is a reproducible finding in men with obesity and hypertension.

No effect of acute tetrahydrobiopterin (BH4) supplementation on vascular dysfunction in the old.

As a deficiency in tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase, has been implicated in the age-related decline in vascular function, this study aimed to determine the impact of acute BH4 supplementation on flow-mediated vasodilation (FMD) in old adults. Two approaches were used: 1) A multiday, double-blind, placebo-controlled, crossover design measuring, FMD [ΔFMD (mm), %FMD (%)] and shear rate area under the curve (SR AUC) in nine old subjects (73 ± 8 yr) with either placebo (placebo) or BH4 (≈10 mg/kg, post), and 2) a single experimental day measuring FMD in an additional 13 old subjects (74 ± 7 yr) prior to (pre) and 4.5 h after ingesting BH4 (≈10 mg/kg). With the first experimental approach, acute BH4 intake did not significantly alter FMD (ΔFMD: 0.17 ± 0.03 vs. 0.13 ± 0.02 mm; %FMD: 3.3 ± 0.61 vs. 2.9 ± 0.4%) or SR AUC (30,280 ± 4,428 vs. 37,877 ± 9,241 s-1) compared with placebo. Similarly, with the second approach, BH4 did not significantly alter FMD (ΔFMD: 0.09 ± 0.02 vs. 0.12 ± 0.03 mm; %FMD: 2.2 ± 0.6 vs. 2.9 ± 0.6%) or SR AUC (37,588 ± 6,753 vs. 28,996 ± 3,735 s-1) compared with pre. Moreover, when the two data sets were combined, resulting in a greater sample size, there was still no evidence of an effect of BH4 on vascular function in these old subjects. Importantly, both plasma BH4 and 7,8-dihydrobiopterin (BH2), the oxidized form of BH4, increased significantly with acute BH4 supplementation. Consequently, the ratio of BH4/BH2, recognized to impact vascular function, was unchanged. Thus, acute BH4 supplementation does not correct vascular dysfunction in the old.NEW & NOTEWORTHY Despite two different experimental approaches, acute BH4 supplementation did not affect vascular function in older adults, as measured by flow-mediated vasodilation. Plasma levels of both BH4 and BH2, the BH4 oxidized form, significantly increased after acute BH4 supplementation, resulting in an unchanged ratio of BH4/BH2, a key determining factor for endothelial nitric oxide synthase coupling. Therefore, likely due to the elevated oxidative stress with advancing age, acute BH4 supplementation does not correct vascular dysfunction in the old.

Effects of indulgent food snacking, with and without exercise training, on body weight, fat mass, and cardiometabolic risk markers in overweight and obese men.

We hypothesized that exercise training would prevent gains in body weight and body fat, and worsening of cardiometabolic risk markers, during a 4-week period of indulgent food snacking in overweight/obese men. Twenty-eight physically inactive men (ages 19-47 yr) with body mass index (BMI) ≥25 kg/m2 consumed 48 donuts (2/day, 6 days/week; ~14,500 kcal total) for 4 weeks while maintaining habitual diet. Men were randomly assigned to control (n = 9), moderate-intensity continuous training (MICT; n = 9), or high-intensity interval training (HIIT; n = 10). Exercise training occurred 4 days/week, ~250 kcal/session. Controls did not increase body weight, body fat, or visceral abdominal fat. This was partially explained by a decrease in self-reported habitual energy (-239 kcal/day, p = 0.05) and carbohydrate (-47 g/day; p = 0.02) intake. Large inter-individual variability in changes in body weight, fat, and fat-free mass was evident in all groups. Fasting blood pressure, and blood concentrations of glucose, insulin, and lipids were unchanged in all groups. Glucose incremental area under the curve during an oral glucose tolerance test was reduced by 25.6% in control (p = 0.001) and 32.8% in MICT (p = 0.01) groups. Flow-mediated dilation (FMD) was not changed in any group. VO2max increased (p ≤ 0.001) in MICT (9.2%) and HIIT (12.1%) groups. We conclude that in physically inactive men with BMI ≥25 kg/m2 , consuming ~14,500 kcal as donuts over 4 weeks did not adversely affect body weight and body fat, or several markers of cardiometabolic risk. Consumption of the donuts may have prevented the expected improvement in FMD with HIIT.

The passive leg movement technique for assessing vascular function: the impact of baseline blood flow.

NEW FINDINGS: What is the central question of this study? The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA): what is the impact of baseline CFA blood flow on the PLM response? What is the main finding and its importance? Although an attenuated PLM response is not an obligatory consequence of increased baseline CFA blood flow, increased blood flow through the deep femoral artery will diminish the response. Care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performing a PLM vascular function assessment. ABSTRACT: The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA). This response is primarily driven by vasodilation of the microvasculature downstream from the deep (DFA) and, to a lesser extent, the superficial (SFA) femoral artery, which facilitate blood flow to the upper and lower leg, respectively. However, the impact of baseline CFA blood flow on the PLM response is unknown. Therefore, to manipulate baseline CFA blood flow, PLM was performed with and without upper and lower leg cutaneous heating in 10 healthy subjects, with blood flow (ultrasound Doppler) and blood pressure (finometer) assessed. Baseline blood flow was significantly increased in the CFA (∼97%), DFA (∼109%) and SFA (∼78%) by upper leg heating. This increase in baseline CFA blood flow significantly attenuated the PLM-induced total blood flow in the DFA (∼62%), which was reflected by a significant fall in blood flow in the CFA (∼49%), but not in the SFA. Conversely, lower leg heating increased blood flow in the CFA (∼68%) and SFA (∼160%), but not in the DFA. Interestingly, this increase in baseline CFA blood flow only significantly attenuated the PLM-induced total blood flow in the SFA (∼60%), and not in the CFA or DFA. Thus, although an attenuated PLM response is not an obligatory consequence of an increase in baseline CFA blood flow, an increase in baseline blood flow through the DFA will diminish the PLM response. Therefore, care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performance of a PLM vascular function assessment.

The dynamic adjustment of mean arterial pressure during exercise: a potential tool for discerning cardiovascular health status.

The regulation of mean arterial pressure (MAP) during exercise has important physiological and clinical implications. Kinetics analysis on numerous physiological variables following the transition from unloaded-to-loaded exercise has revealed important information regarding their control. Surprisingly, the dynamic response of MAP during this transition remains to be quantified. Therefore, ten healthy participants (5/5 M/F, 24 ± 3 yr) completed repeated transitions from unloaded to moderate- and heavy-intensity dynamic single-leg knee-extensor exercise to investigate the on-kinetics of MAP. Following the transition to loaded exercise, MAP increased in a first-order dynamic manner, subsequent to a time delay (moderate: 23 ± 10; heavy: 19 ± 9 s, P > 0.05) at a speed (τ, moderate: 59 ± 30; heavy: 66 ± 19 s, P > 0.05), which did not differ between intensities, but the MAP amplitude was doubled during heavy-intensity exercise (moderate: 12 ± 5; heavy: 24 ± 8 mmHg, P < 0.001). The reproducibility [coefficient of variation (CV)] during heavy intensity for unloaded baseline, amplitude, and mean response time, when assessed as individual transitions, was 7 ± 1%, 18 ± 2%, and 25 ± 4%, respectively. Averaging two transitions improved the CVs to 4 ± 1%, 8 ± 2%, and 13 ± 3%, respectively. Preliminary findings supporting the clinical relevance of evaluating MAP kinetics in middle-aged hypertensive (n = 5) and, age-matched, normotensive (n = 5) participants revealed an exaggerated MAP response in both older groups (P < 0.05), but the MAP response was slowed only for the patients with hypertension (P < 0.05). It is concluded that kinetics modeling of MAP is practical for heavy-intensity knee-extensor exercise and may provide insight into cardiovascular health and the effect of aging.NEW & NOTEWORTHY Kinetics analysis of physiological variables following workload transitions provides important information, but this has not been performed on mean arterial pressure (MAP), despite the clear clinical importance of this variable. This investigation reveals that kinetic modeling of MAP following unloaded-to-loaded knee-extensor exercise is practical and repeatable. Additional preliminary findings in hypertensive and, age-matched, normotensive subjects suggest that MAP kinetics may provide insight into cardiovascular health and the effect of aging.

Vascular function in continuous-flow left ventricular assist device recipients: effect of a single pulsatility treatment session.

Vascular function is further attenuated in patients with chronic heart failure implanted with a continuous-flow left ventricular assist device (LVAD), likely due to decreased arterial pulsatility, and this may contribute to LVAD-associated cardiovascular complications. However, the impact of increasing pulsatility on vascular function in this population is unknown. Therefore, 15 LVAD recipients and 15 well-matched controls underwent a 45-min, unilateral, arm pulsatility treatment, evoked by intermittent cuff inflation/deflation (2-s duty cycle), distal to the elbow. Vascular function was assessed by percent brachial artery flow-mediated dilation (%FMD) and reactive hyperemia (RH) (Doppler ultrasound). Pretreatment, %FMD (LVAD: 4.0 ± 1.7; controls: 4.2 ± 1.4%) and RH (LVAD: 340 ± 101; controls: 308 ± 94 mL) were not different between LVAD recipients and controls; however, %FMD/shear rate was attenuated (LVAD: 0.10 ± 0.04; controls: 0.17 ± 0.06%/s-1, P < 0.05). The LVAD recipients exhibited a significantly attenuated pulsatility index (PI) compared with controls prior to treatment (LVAD: 2 ± 2; controls: 15 ± 7 AU, P < 0.05); however, during the treatment, PI was no longer different (LVAD: 37 ± 38; controls: 36 ± 14 AU). Although time to peak dilation and RH were not altered by the pulsatility treatment, %FMD (LVAD: 7.0 ± 1.8; controls: 7.4 ± 2.6%) and %FMD/shear rate (LVAD: 0.19 ± 0.07; controls: 0.33 ± 0.15%/s-1) increased significantly in both groups, with, importantly, %FMD/shear rate in the LVAD recipients being restored to that of the controls pretreatment. This study documents that a localized pulsatility treatment in LVAD recipients and controls can recover local vascular function, an important precursor to the development of approaches to increase systemic pulsatility and reduce systemic vascular complications in LVAD recipients.

Sacubitril-valsartan improves conduit vessel function and functional capacity and reduces inflammation in heart failure with reduced ejection fraction.

The Prospective comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan (trade name Entresto), but the physiological processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF (n = 11, 10 M/1 F, left ventricular ejection fraction = 27 ± 8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function [brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)], functional capacity [six-minute walk test (6MWT) distance], and the proinflammatory biomarkers tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and at 1, 2, and 3 mo of treatment. %FMD improved after 1 mo of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25 ± 1.75%; 1 mo: 5.23 ± 2.36%; 2 mo: 5.81 ± 1.79%; 3 mo: 6.35 ± 2.77%), whereas RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420 ± 92 m; 1 mo: 436 ± 98 m; 2 mo: 465 ± 115 m; 3 mo: 460 ± 110 m), and there was a sustained reduction in TNF-α (baseline: 2.38 ± 1.35 pg/mL; 1 mo: 2.06 ± 1.52 pg/mL; 2 mo: 1.95 ± 1.34 pg/mL; 3 mo: 1.92 ± 1.37 pg/mL) and a reduction in IL-18 at month 3 (baseline: 654 ± 150 pg/mL; 1 mo: 595 ± 140 pg/mL; 2 mo: 601 ± 176 pg/mL; 3 mo: 571 ± 127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF.NEW & NOTEWORTHY We observed an approximately twofold improvement in conduit vessel function (brachial artery FMD), increased functional capacity (6MWT distance), and a reduction in inflammation (TNF-α and IL-18) following 3 mo of sacubitril-valsartan therapy. These findings provide important new information concerning the physiological mechanisms by which this new drug class provokes favorable changes in HFrEF pathophysiology.

The role of the endothelium in the hyperemic response to passive leg movement: looking beyond nitric oxide.

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P-450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBFAUC)] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271 ± 97 mL, P > 0.05) or sPLM (LBFAUC: 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P-450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.

Chronic antioxidant administration restores macrovascular function in patients with heart failure with reduced ejection fraction.

NEW FINDINGS: What is the central question of this study? We aimed to examine oxidative stress, antioxidant capacity and macro- and microvascular function in response to 30 days of oral antioxidant administration in patients with heart failure with reduced ejection fraction. What is the main finding and its importance? We observed an approximately twofold improvement in macrovascular function, assessed via brachial artery flow-mediated dilatation, and a reduction in oxidative stress after antioxidant administration in patients with heart failure with reduced ejection fraction. The improvement in macrovascular function was reversed 1 week after treatment cessation. These findings have identified the potential of oral antioxidant administration to optimize macrovascular health in this patient group. ABSTRACT: Heart failure with reduced ejection fraction (HFrEF) is characterized by macrovascular dysfunction and elevated oxidative stress that may be mitigated by antioxidant (AOx) administration. In this prospective study, we assessed flow-mediated dilatation (FMD) and reactive hyperaemia responses in 14 healthy, older control participants and 14 patients with HFrEF, followed by 30 days of oral AOx administration (1 g vitamin C, 600 I.U. vitamin E and 0.6 g α-lipoic acid) in the patient group. Blood biomarkers of oxidative stress (malondialdehyde) and AOx capacity (ferric reducing ability of plasma) were also assessed. Patients with HFrEF had a lower %FMD (2.63 ± 1.57%) than control participants (5.62 ± 2.60%), and AOx administration improved %FMD in patients with HFrEF (30 days, 4.90 ± 2.38%), effectively restoring macrovascular function to that of control participants. In a subset of patients, we observed a progressive improvement in %FMD across the treatment period (2.62 ± 1.62, 4.23 ± 2.69, 4.33 ± 2.24 and 4.97 ± 2.56% at days 0, 10, 20 and 30, respectively, n = 12) that was abolished 7 days after treatment cessation (2.99 ± 1.78%, n = 9). No difference in reactive hyperaemia was evident between groups or as a consequence of the AOx treatment. Ferric reducing ability of plasma levels increased (from 6.08 ± 2.80 to 6.70 ± 1.59 mm, day 0 versus 30) and malondialdehyde levels decreased (from 6.81 ± 2.80 to 6.22 ± 2.84 µm, day 0 versus 30) after treatment. These findings demonstrate the efficacy of chronic AOx administration in attenuating oxidative stress, improving AOx capacity and restoring macrovascular function in patients with HFrEF.

Imaging transcranial Doppler ultrasound to measure middle cerebral artery blood flow: the importance of measuring vessel diameter.

Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆-4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆-0.88 ± 4.7 cm/s) (P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) (P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆-5 ± 130 ml/min) (P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.

The passive leg movement technique for assessing vascular function: defining the distribution of blood flow and the impact of occluding the lower leg.

NEW FINDINGS: What is the central question of this study? What is the distribution of the hyperaemic response to passive leg movement (PLM) in the common (CFA), deep (DFA) and superficial (SFA) femoral arteries? What is the impact of lower leg cuff-induced blood flow occlusion on this response? What is the main finding and its importance? Of the total blood that passed through the CFA, the majority was directed to the DFA and this was unaffected by cuffing. As a small fraction does pass through the SFA to the lower leg, cuffing during PLM should be considered to emphasize the thigh-specific hyperaemia. ABSTRACT: It has yet to be quantified how passive leg movement (PLM)-induced hyperaemia, an index of vascular function, is distributed beyond the common femoral artery (CFA), into the deep femoral (DFA) and the superficial femoral (SFA) arteries, which supply blood to the thigh and lower leg, respectively. Furthermore, the impact of cuffing the lower leg, a common practice, especially with drug infusions during PLM, on the hyperaemic response is, also, unknown. Therefore, PLM was performed with and without cuff-induced blood flow (BF) occlusion to the lower leg in 10 healthy subjects, with BF assessed by Doppler ultrasound. In terms of BF distribution during PLM, of the 380 ± 191 ml of blood that passed through the CFA, 69 ± 8% was directed to the DFA, while only 31 ± 8% passed through the SFA. Cuff occlusion of the lower leg significantly attenuated the PLM-induced hyperaemia through the SFA (∼30%), which was reflected by a fall in BF through the CFA (∼20%), but not through the DFA. Additionally, cuff occlusion significantly attenuated the PLM-induced peak change in BF (BFΔpeak ) in the SFA (324 ± 159 to 214 ± 114 ml min-1 ), which was, again, reflected in the CFA (1019 ± 438 to 833 ± 476 ml min-1 ), but not in the DFA. Thus, the PLM-induced hyperaemia predominantly passes through the DFA and this was unaltered by cuffing. However, as a small fraction of the PLM-induced hyperaemia does pass through the SFA to the lower leg, cuffing the lower leg during PLM should be considered to emphasize thigh-specific hyperaemia in the PLM assessment of vascular function.

Strong Relationship Between Vascular Function in the Coronary and Brachial Arteries.

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 µg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

High-intensity interval exercise attenuates but does not eliminate endothelial dysfunction after a fast food meal.

We investigated whether two different bouts of high-intensity interval exercise (HIIE) could attenuate postprandial endothelial dysfunction. Thirteen young (27 ± 1 yr), nonexercise-trained men underwent three randomized conditions: 1) four 4-min intervals at 85-95% of maximum heart rate separated by 3 min of active recovery (HIIE 4 × 4), 2) 16 1-min intervals at 85-95% of maximum heart rate separated by 1 min of active recovery (HIIE 16 × 1), and 3) sedentary control. HIIE was performed in the afternoon, ~18 h before the morning fast food meal (1,250 kcal, 63g of fat). Brachial artery flow-mediated dilation (FMD) was performed before HIIE ( baseline 1), during fasting before meal ingestion ( baseline 2), and 30 min, 2 h, and 4 h postprandial. Capillary glucose and triglycerides were assessed at fasting, 30 min, 1 h, 2 h, and 4 h (triglycerides only). Both HIIE protocols increased fasting FMD compared with control (HIIE 4 × 4: 6.1 ± 0.4%, HIIE 16 × 1: 6.3 ± 0.5%, and control: 5.1 ± 0.4%, P < 0.001). For both HIIE protocols, FMD was reduced only at 30 min postprandial but never fell below baseline 1 or FMD during control at any time point. In contrast, control FMD decreased at 2 h (3.8 ± 0.4%, P < 0.001) and remained significantly lower than HIIE 4 × 4 and 16 × 1 at 2 and 4 h. Postprandial glucose and triglycerides were unaffected by HIIE. In conclusion, HIIE performed ~18 h before a high-energy fast food meal can attenuate but not entirely eliminate postprandial decreases in FMD. This effect is not dependent on reductions in postprandial lipemia or glycemia. NEW & NOTEWORTHY Two similar high-intensity interval exercise (HIIE) protocols performed ∼18 h before ingestion of a high-energy fast food meal attenuated but did not entirely eliminate postprandial endothelial dysfunction in young men largely by improving fasting endothelial function. Both HIIE protocols produced essentially identical results, suggesting high reproducibility of HIIE effects.

The effect of exercise training on biventricular myocardial strain in heart failure with preserved ejection fraction.

AIMS: High-intensity interval training (HIIT) improves peak oxygen uptake and left ventricular diastology in patients with heart failure with preserved ejection fraction (HFpEF). However, its effects on myocardial strain in HFpEF remain unknown. We explored the effects of HIIT and moderate-intensity aerobic continuous training (MI-ACT) on left and right ventricular strain parameters in patients with HFpEF. Furthermore, we explored their relationship with peak oxygen uptake (VO2peak ). METHODS AND RESULTS: Fifteen patients with HFpEF (age = 70 ± 8.3 years) were randomized to either: (i) HIIT (4 × 4 min, 85-90% peak heart rate, interspersed with 3 min of active recovery; n = 9) or (ii) MI-ACT (30 min at 70% peak heart rate; n = 6). Patients were trained 3 days/week for 4 weeks and underwent VO2peak testing and 2D echocardiography at baseline and after completion of the 12 sessions of supervised exercise training. Left ventricular (LV) and right ventricular (RV) average global peak systolic longitudinal strain (GLS) and peak systolic longitudinal strain rate (GSR) were quantified. Paired t-tests were used to examine within-group differences and unpaired t-tests used for between-group differences (α = 0.05). Right ventricular average global peak systolic longitudinal strain improved significantly in the HIIT group after training (pre = -18.4 ± 3.2%, post = -21.4 ± 1.7%; P = 0.02) while RV-GSR, LV-GLS, and LV-GSR did not (P > 0.2). No significant improvements were observed following MI-ACT. No significant between-group differences were observed for any strain measure. ΔLV-GLS and ΔRV-GLS were modestly correlated with ΔVO2peak (r = -0.48 and r = -0.45; P = 0.1, respectively). CONCLUSIONS: In patients with HFpEF, 4 weeks of HIIT significantly improved RV-GLS.

Adaptive goal setting and financial incentives: a 2 × 2 factorial randomized controlled trial to increase adults' physical activity.

BACKGROUND: Emerging interventions that rely on and harness variability in behavior to adapt to individual performance over time may outperform interventions that prescribe static goals (e.g., 10,000 steps/day). The purpose of this factorial trial was to compare adaptive vs. static goal setting and immediate vs. delayed, non-contingent financial rewards for increasing free-living physical activity (PA). METHODS: A 4-month 2 × 2 factorial randomized controlled trial tested main effects for goal setting (adaptive vs. static goals) and rewards (immediate vs. delayed) and interactions between factors to increase steps/day as measured by a Fitbit Zip. Moderate-to-vigorous PA (MVPA) minutes/day was examined as a secondary outcome. RESULTS: Participants (N = 96) were mainly female (77%), aged 41 ± 9.5 years, and all were insufficiently active and overweight/obese (mean BMI = 34.1 ± 6.2). Participants across all groups increased by 2389 steps/day on average from baseline to intervention phase (p < .001). Participants receiving static goals showed a stronger increase in steps per day from baseline phase to intervention phase (2630 steps/day) than those receiving adaptive goals (2149 steps/day; difference = 482 steps/day, p = .095). Participants receiving immediate rewards showed stronger improvement (2762 step/day increase) from baseline to intervention phase than those receiving delayed rewards (2016 steps/day increase; difference = 746 steps/day, p = .009). However, the adaptive goals group showed a slower decrease in steps/day from the beginning of the intervention phase to the end of the intervention phase (i.e. less than half the rate) compared to the static goals group (-7.7 steps vs. -18.3 steps each day; difference = 10.7 steps/day, p < .001) resulting in better improvements for the adaptive goals group by study end. Rate of change over the intervention phase did not differ between reward groups. Significant goal phase x goal setting x reward interactions were observed. CONCLUSIONS: Adaptive goals outperformed static goals (i.e., 10,000 steps) over a 4-month period. Small immediate rewards outperformed larger, delayed rewards. Adaptive goals with either immediate or delayed rewards should be preferred for promoting PA. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02053259 registered prospectively on January 31, 2014.