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The current investigation has demonstrated that l-Cit administration may improve brachial artery endothelium-dependent vasodilation, upper and lower limb microvascular function, and physical capacity in patients with HFpEF, highlighting the potential therapeutic potential of interventions targeting the l-Arg-NO signaling cascade to improve outcomes in this patient group.

Remnant cholesterol (RC) and non-high-density lipoprotein cholesterol (non-HDL-C) may contribute to the residual risk for atherosclerotic cardiovascular disease. High cardiorespiratory fitness (CRF) is associated with favorable traditional lipid profiles, but its relation with RC and non-HDL-C remains unclear. We analyzed cross-sectional data on 4,613 healthy men (mean age 49 years). CRF was measured using peak oxygen uptake during incremental exercise testing and categorized into quartiles. RC was estimated as total cholesterol minus HDL-C and low-density lipoprotein cholesterol, and elevated RC was defined as ≥38 mg/100 ml (90 percentile). Non-HDL-C was calculated as total cholesterol minus HDL-C, and high non-HLD-C was defined as ≥190 mg/100 ml. CRF was inversely associated with RC (β -0.31, 95% confidence interval [CI] -0.39 to -0.24) and non-HDL-C (β -0.34, 95% CI -0.57 to -0.11) after adjustment for several risk factors. Each metabolic equivalent increment in CRF was associated with lower odds of having elevated RC (odds ratio [OR] 0.85, 95% CI 0.77 to 0.93) and non-HDL-C (OR 0.93, 95% CI 0.85 to 1.00) in multivariable analysis. Compared with the bottom quartile, the top quartile of CRF had significantly lower odds of elevated RC (OR 0.63, 95% CI 0.45 to 0.88) and non-HDL-C (OR 0.68, 95% CI 0.51 to 0.91). In conclusion, higher CRF was independently associated with lower levels of RC and non-HDL-C and lower odds of the prevalence of elevated RC and non-HDL-C in healthy men.

Background: Achieving healthy vascular aging (HVA) is important for decelerating age-related cardiovascular disease risk. We evaluated the interplay between HVA, cardiorespiratory fitness (CRF), and subclinical atherosclerosis. Methods: We analyzed data on 3722 men who underwent cardiopulmonary exercise testing in a health examination program. HVA was defined as blood pressure 0 and ≥100 and a mean carotid artery intima-media thickness (CIMT) >75th percentile for each age group as well as >0.8 mm of CIMT. Separate and joint associations of HVA and CRF with subclinical atherosclerosis were evaluated. Results: Each 1 metabolic equivalent increment in CRF was associated with 23% higher odds for having HVA. HVA was associated with lower odds of coronary artery calcification but not CIMT. CRF modified the association between HVA and CIMT>0.8 mm (interaction: P =0.01); HVA was associated with lower odds of CIMT>0.8 mm in fit men with no significant association between HVA and CIMT>0.8 mm in unfit men. Compared with no HVA and being unfit, HVA and being fit was associated with lower odds of subclinical atherosclerosis, but there was no significant association between HVA and being unfit with subclinical atherosclerosis. Conclusions: HVA and higher CRF are each associated with a lower risk of subclinical atherosclerosis in men. Higher CRF is associated with a higher prevalence of HVA and may modify the association between HVA and subclinical atherosclerosis.

Exercise intolerance is a well-described characteristic of heart failure with preserved ejection fraction (HFpEF), but whether disease-related changes in autonomic function contribute to impaired cardiovascular control during exercise is not well understood. Thus, we used a combination of static handgrip exercise (HG) and post-exercise ischemia (PEI) to examine the pressor response to exercise and isolate the skeletal muscle metaboreflex, respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were assessed during 2-min of static HG at 30 and 40% of maximum voluntary contraction (MVC) and subsequent PEI in sixteen patients with HFpEF and seventeen healthy, similarly aged controls. Changes in MAP were lower in patients with HFpEF compared to controls during both 30%MVC (Δ11 ± 7 vs. Δ15 ± 8 mmHg) and 40%MVC (Δ19 ± 14 vs. Δ30 ± 8 mmHg), and a similar pattern of response was evident during PEI (30%MVC: Δ8 ± 5 vs. Δ12 ± 8 mmHg; 40%MVC: Δ13 ± 10 vs. Δ18 ± 9 mmHg) (group effect: p=0.048 and p=0.020 at 30% and 40% MVC, respectively). Changes in HR, CO, and TPR did not differ between groups during HG or PEI (p>0.05). Taken together, these data suggest a reduced pressor response to static muscle contractions in patients with HFpEF compared to similarly aged controls that may be mediated, in part, by a blunted muscle metaboreflex. These findings support a disease-related dysregulation in neural cardiovascular control that may contribute to the extreme exercise intolerance present in this patient group.

Background: HFpEF is characterized by peripheral vascular dysfunction, which likely underlies clinical presentations such as dyspnea on exertion and severe exercise intolerance in this population. HMG-CoA reductase inhibitors, also known as “statins,” can exert beneficial pleiotropic effects on the vasculature that may be related to improvements in nitric oxide (NO) signalling. However, it has yet to be investigated whether statin therapy can improve vascular function in patients with HFpEF. We hypothesized that 30-day statin therapy would improve upper limb conduit vessel and microvascular function, as determined by brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH), respectively, and improve locomotor muscle microvascular responsiveness, as determined by passive limb movement (PLM). Methods: Using a double-blind, parallel design, patients with HFpEF were studied before and after randomization to 30 days of statin therapy (atorvastatin, 10 mg; QD, n = 4) or placebo ( n = 3). FMD, RH, and PLM testing was performed via ultrasonography according to published guidelines. Results: Compared to baseline values, FMD tended to improve following statin therapy (2.8 ± 2.4% to 4.7 ± 1.5%, day 0 to day 30, P=0.06), with no change following placebo (P=0.87). FMD adjusted for shear also tended to improve following statin therapy (0.09 ± 0.08AU to 0.15 ± 0.03AU, day 0 to day 30, P=0.07), with no change following placebo (P=0.79). RH was unchanged following both statin (P=0.24) and placebo (P=0.31) interventions. PLM AUC appeared to improve following statin therapy (98 ± 62ml to 184 ± 111ml, day 0 to day 30, P=0.22), with no change following placebo (P=0.64). The peak blood flow response to PLM was unchanged in both statin (P=0.31) and placebo (P=0.28) groups. Conclusions: While no statistically significant differences were observed, qualitative analyses suggest that statin therapy may improve upper limb conduit vessel function and locomotor muscle microvascular responsiveness in patients with HFpEF, supporting the potential efficacy of this drug class to improve vascular function. These improvements in vascular reactivity provide preliminary evidence for improved NO bioavailability that may translate to improvements in functional capacity and exercise tolerance in this patient group. Funded in part by grants from the U.S. Department of Veteran’s Affairs (1I01CX002152, D.W.W., 1IK2RX003670, K.B.) and the National Institutes of Health (5T32HL139451, K.B.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: The arterial baroreflex (ABR) plays an important role in evoking appropriate cardiovascular adjustments in response to perturbations such as exercise. The ABR control of heart rate (HR) becomes attenuated with advancing age and in a variety of patient populations, but limited information is available in patients with heart failure with preserved ejection fraction (HFpEF). The present study tested the hypothesis that the ABR control of HR is attenuated to a greater extent in patients with HFpEF compared to older and young controls. Methods: Six patients with HFpEF (71±6 years; 35.3±6.6 kg/m2), 4 older controls (68±4 years; 25.1±3.4 kg/m2), and 7 young controls (27±4 years; 26.6±3.9 kg/m2) underwent sequential bolus infusions of sodium nitroprusside (50-100 μg) and phenylephrine (150 μg) (modified Oxford technique) to provoke acute hypotension (“BP falls”) and hypertension (“BP rises”), respectively. Cardiac baroreflex gain was quantified as the weighted linear regression slope between the R-R interval and systolic blood pressure (BP). Results: Compared to young controls (10.7±3.4 ms/mmHg), overall cardiac baroreflex gain was reduced in older controls (3.4±1.6 ms/mmHg) and patients with HFpEF (2.1±1.8 ms/mmHg) (p0.05); however, responses in patients with HFpEF were attenuated compared to young controls 10.7±5.8 ms/mmHg) (p This work was funded in part by the U.S. Department of Veterans Affairs (RX001311, to D.W.W.; IK2RX003670, to K.B.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heart failure with preserved ejection fraction (HFpEF) is characterized by peripheral vascular dysregulation at both rest and during exercise. Prior studies have demonstrated that blood flow to skeletal muscle is closely regulated by sympathetic (α-adrenergic) vasoconstriction and the interaction of vasoactive substances released locally during exercise that counteract α-adrenergic vasoconstriction. This phenomenon, known as “functional sympatholysis” helps facilitate exercise hyperemia and has been shown to decline via aging and disease-related changes in α1-adrenergic function but this has not been studied in HFpEF. Thus, the overall objective of this study was to characterize peripheral α1-adrenergic vasoconstriction in HFpEF. We hypothesized that both resting α1-mediated vasoconstriction and the magnitude of functional sympatholysis would be diminished in HFpEF compared to healthy, age-matched control (CON) subjects.Six patients with HFpEF (3 male, 70±3 yrs) and six CON (3 male, 67±1 yrs) completed this study. Leg blood flow (LBF, ultrasound Doppler) was evaluated at rest and during dynamic single leg knee-extension exercise (0, 5 and 10 Watts) before and after local, intra-arterial administration of Phenylephrine (PE, α1-adrenergic agonist). PE-mediated changes in LBF (%Δ) at rest and during exercise were compared between groups. The magnitude of functional sympatholysis was calculated as the difference between PE-induced %Δ LBF from rest to exercise.At rest, the PE-induced %Δ LBF was smaller in HFpEF (HFpEF: -17±2% vs. CON: -31±8%, P=0.01). While PE-induced %Δ LBF were similar between groups during exercise, when these responses were compared to %Δ LBF at rest, the calculated magnitude of sympatholysis was significantly reduced in HFpEF (0W: -4±3%, 5W: -5±4%, 10W: -8±3%) compared to CON (0W: -17±7%, 5W: -20±8%, 10W: -25±6%). These data demonstrate a marked diminution in both α1-adrenergic responsiveness at rest and the ability to attenuate α1-adrenergic mediated vasoconstriction during exercise (functional sympatholysis) in patients with HFpEF. Diminished α1-adrenergic signaling and impaired functional sympatholysis may represent an important aspect of HFpEF pathophysiology that likely contribute to vascular dysregulation in this patient group. Funded in part by grants from the National Institutes of Health (T32HL139451) and the Veterans Health Administration (I01RX001311, IK2RX003670, IK2CX002114). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Obesity is now considered a primary comorbidity in heart failure with preserved ejection fraction (HFpEF) pathophysiology, mediated largely by systemic inflammation. Although there is accumulating evidence for a disease-related dysregulation of blood flow during exercise in this patient group, the role of obesity in the hemodynamic response to exercise remains largely unknown. Small muscle mass handgrip (HG) exercise was used to evaluate exercising muscle blood flow in nonobese (BMI < 30 kg/m(2), n = 14) and obese (BMI > 30 kg/m(2), n = 40) patients with HFpEF. Heart rate (HR), stroke index (SI), cardiac index (CI), mean arterial pressure (MAP), forearm blood flow (FBF), and vascular conductance (FVC) were assessed during progressive intermittent HG exercise [15%–30%–45% maximal voluntary contraction (MVC)]. Blood biomarkers of inflammation [C-reactive protein (CRP) and interleukin-6 (IL-6)] were also determined. Exercising FBF was reduced in obese patients with HFpEF at all work rates (15%: 304 ± 42 vs. 229 ± 15 mL/min; 30%: 402 ± 46 vs. 300 ± 18 mL/min; 45%: 484 ± 55 vs. 380 ± 23 mL/min, nonobese vs. obese, P = 0.025), and was negatively correlated with BMI (R = −0.47, P < 0.01). In contrast, no differences in central hemodynamics (HR, SI, CI, and MAP) were found between groups. Proinflammatory biomarkers were markedly elevated in patients with obesity (CRP: 2,133 ± 418 vs. 4,630 ± 590 ng/mL, P = 0.02; IL-6: 2.9 ± 0.3 vs. 5.2 ± 0.7 pg/mL, nonobese vs. obese, P = 0.04), and both biomarkers were positively correlated with BMI (CRP: R = 0.40, P = 0.03; IL-6: R = 0.57, P < 0.01). Together, these findings demonstrate the presence of obesity and an accompanying milieu of systemic inflammation as important factors in the dysregulation of exercising muscle blood flow in patients with HFpEF. NEW & NOTEWORTHY Obesity is the primary comorbid condition in HFpEF pathophysiology, but the role of adiposity on the peripheral circulation is not well understood. The present study identified a 30%–40% reduction in forearm blood flow during handgrip exercise, accompanied by a marked elevation in proinflammatory plasma biomarkers, in obese patients with HFpEF compared with their nonobese counterparts. These findings suggest an exaggerated dysregulation in exercising muscle blood flow associated with the obese HFpEF phenotype.

We examined the efficacy of ankle bathing versus aerobic exercise to improve vascular function in young adults who were randomized to aerobic exercise (AE) (n = 13, 40%–60% of heart rate reserve), ankle bathing (AB) (n = 15, 43 °C), or a control condition (CON) (n = 14, ankle bathing, 36 °C) for 40 min. Conduit vessel function [brachial artery flow-mediated dilation (FMD)], carotid and femoral artery blood flow and shear rate (SR), and arterial stiffness [carotid-to-femoral pulse wave velocity (cf-PWV), augmentation index (AIx@75), β-stiffness index, and arterial compliance] were evaluated. Compared with CON, AE and AB increased FMD at 30 min and 90 min (interaction: p < 0.05); AB decreased carotid artery blood flow and SR at 30 min, while both AE and AB increased femoral artery blood flow and SR at 30 min and 90 min (interaction: p < 0.05); AE and AB decreased cf-PWV and AIx@75 at 30 min and 90 min (interaction: p < 0.05); and AE improved both carotid and femoral β-stiffness index and arterial compliance, while AB reduced β-stiffness index and increased arterial compliance only in the femoral artery (interaction: p < 0.05). These findings suggest that ankle bathing may serve as an alternative strategy for enhancing vascular function.Novelty: We observed similar improvements in conduit vessel function, femoral artery blood flow and shear rate, and arterial stiffness following ankle bathing and acute aerobic exercise in young adults. These findings have identified ankle bathing as a potential therapeutic strategy for enhancing vascular function, which may be particularly relevant for those with limited ability to engage in regular aerobic exercise.

Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that began spreading globally in late 2019. While most cases of COVID-19 present with mild to moderate symptoms, COVID-19 was the third leading cause of mortality in the United States in 2020 and 2021. Though COVID-19 affects individuals of all races and ethnicities, non-Hispanic Black and Hispanic/Latinx populations are facing an inequitable burden of COVID-19 characterized by an increased risk for hospitalization and mortality. Importantly, non-Hispanic Black and Hispanic/Latinx adults have also faced a greater risk of non-COVID-19-related mortality (e.g., from cardiovascular disease/CVD) during the pandemic. Contributors to the racial disparities in morbidity and mortality during the pandemic are multi-factorial as we discuss in our companion article on social determinants of health. However, profound racial variation in the prevalence of CVD and metabolic diseases may serve as a key driver of worse COVID-19-related and non-COVID-19-related health outcomes among racial and ethnic minority groups. Within this review, we provide data emphasizing the inequitable burden of CVD and metabolic diseases among non-Hispanic Black and Hispanic/Latinx populations. We also discuss the pathophysiology of these conditions, with a focus on how aberrant physiological alterations in the context of CVD and metabolic diseases manifest to increase susceptibility to severe COVID-19.

Racial and ethnic-related health disparities in the United States have been intensified by the greater burden of Coronavirus Disease 2019 (COVID-19) in racial and ethnic minority populations. Compared to non-Hispanic White individuals, non-Hispanic Black and Hispanic/Latinx individuals infected by COVID-19 are at greater risk for hospitalization, intensive care unit admission, and death. There are several factors that may contribute to disparities in COVID-19-related severity and outcomes in these minority populations, including the greater burden of cardiovascular and metabolic diseases as discussed in our companion review article. Social determinants of health are a critical, yet often overlooked, contributor to racial and ethnic-related health disparities in non-Hispanic Black and Hispanic/Latinx individuals relative to non-Hispanic White individuals. Thus, the purpose of this review is to focus on the essential role of social factors in contributing to health disparities in chronic diseases and COVID-19 outcomes in minority populations. Herein, we begin by focusing on structural racism as a social determinant of health at the societal level that contributes to health disparities through downstream social level (e.g., occupation and residential conditions) and individual level health behaviors (e.g., nutrition, physical activity, and sleep). Lastly, we conclude with a discussion of practical applications and recommendations for future research and public health efforts that seek to reduce health disparities and overall disease burden.

In recent years, the traditional, unspoken assumption in published biomedical research studies that the young, healthy (usually white) male is the “default human” has received increasing scrutiny and criticism. The historical underrepresentation of female participants in biomedical research has been increasingly recognized and addressed, including with the current call for papers at the American Journal of Physiology-Heart and Circulatory Physiology. Our goal in the present Perspectives is to discuss the topic of terminology (man/woman vs. male/female) for human research participants when considering sex as a biological variable. This important consideration is consistent with the importance of gender identity and related topics to psychological, emotional, and physical health. Just as pronouns are important, so is appropriate terminology when referring to human research volunteers. Despite some disagreement regarding terminology between our two groups of authors, we provide consensus recommendations. Importantly, we all agree that the most vital aspect of the present discussion is the broader focus on sex as a biological variable and appropriate inclusion of biological sex in in vitro, preclinical, and human research studies.

While there is emerging evidence of peripheral microvascular dysfunction in patients with heart failure with preserved ejection fraction that may be related to systemic inflammation and redox imbalance, disease-related changes in locomotor muscle microvascular responsiveness has not been determined. This study combined passive leg movement and biomarker assessments of inflammation and oxidative damage to determine the magnitude and mechanisms of lower limb microvascular function in patients with heart failure with preserved ejection fraction (71±1yrs; n=44) compared to healthy, similarly-aged controls (68±2yrs; n=39). Leg blood flow, heart rate, mean arterial pressure, and stroke volume were assessed, and plasma biomarkers of inflammation and oxidative damage were also determined. A significantly attenuated passive leg movement-induced peak change in leg blood flow (263±25 vs. 371±31 mL/min, heart failure with preserved ejection fraction vs. control) and leg vascular conductance (2.99±0.32 vs. 3.88±0.34 mL/min/mmHg, heart failure with preserved ejection fraction vs. control) was observed in patients compared to controls. Similarly, the total hyperemic response to passive leg movement, expressed as leg blood flow(AUC) and leg vascular conductance(AUC), was ~40% less in patients with heart failure with preserved ejection fraction vs. control. Significantly greater C-reactive protein, interleukin 6, and malondialdehyde were observed in patients with heart failure with preserved ejection fraction, but were not correlated with passive leg movement responses. These data provide new evidence of a decline in lower limb microvascular function within a milieu of vascular inflammation that may contribute to locomotor muscle dysfunction in patients with heart failure with preserved ejection fraction.

There is accumulating evidence for both peripheral vascular dysfunction and impaired functional capacity in patients with heart failure with a preserved ejection fraction (HFpEF). While derangements in the L-Arginine-nitric oxide (L-Arg-NO) pathway are likely to contribute to these aspects of HFpEF pathophysiology, the impact of increased NO substrate on vascular health and physical capacity has not been evaluated in this patient population. Thus, using a single-arm study design, we evaluated the impact of enteral L-Citrulline (L-Cit, 6g/day for 7 days), a precursor for L-Arg biosynthesis, on vascular function (flow-mediated dilation [FMD], reactive hyperemia [RH], and passive limb movement [PLM]), functional capacity (six-minute walk test [6MWT]) and biomarkers of L-Arg-NO signalling in 14 patients with HFpEF (n = 14, 4M/10F, 70±10yrs, EF: 66±7%). Compared to baseline (0d), 7 days of L-Cit administration improved FMD (0d: 2.5±0.5%, 7d: 4.7±0.9%), RH (0d: 450±46ml, 7d: 574±62ml), PLM area-under-the-curve (0d: 139±36ml, 7d: 198±32ml), and 6MWT distance (0d: 377±27m, 7d: 397±27m) (p0.05). An increase in plasma L-Cit (0d: 42 ± 3µM/L, 7d: 370 ± 60 µM/L), L-Arg (0d: 65 ± 8µM/L, 7d: 257 ± 25µM/L), and the ratio of L-Arg to asymmetric dimethylarginine (ADMA) (0d: 136±14AU, 7d: 481±50AU) (p0.05) was also observed. Though preliminary in nature, these functional and biomarker assessments demonstrate a potential benefit of L-Cit administration in patients with HFpEF, findings that provide new insight into the mechanisms that govern vascular and physical dysfunction in this patient group.

INTRODUCTION Adults with obesity are at an increased risk of incident hypertension. Regular aerobic exercise is recommended for the prevention and treatment of hypertension, but whether young adults with obesity exhibit impaired postexercise blood pressure (BP) and vascular responses remains unclear. PURPOSE We tested the hypothesis that young adults with obesity exhibit attenuated postexercise hypotension (PEH) and postexercise peripheral vasodilation compared with young adults without obesity. METHODS Thirty-six normotensive adults without and with obesity (11 men and 7 women per group) underwent measurements of brachial and central BP, and leg blood flow (Doppler ultrasound) at baseline and at 30, 60, and 90 min after acute 1-h moderate-intensity cycling. Leg vascular conductance (LVC) was calculated as flow/mean arterial pressure. RESULTS Both groups exhibited similar brachial and central PEH (peak change from baseline, -2 and -4 mm Hg for brachial and central systolic BPs, respectively, for both groups; time effect, P < 0.05). Both groups also exhibited postexercise peripheral vasodilation, assessed via LVC (time effect, P < 0.05), but its overall magnitude was smaller in young adults with obesity (LVC change from baseline, +47% ± 37%, +29% ± 36%, and +20% ± 29%) compared with young adults without obesity (LVC change from baseline, +88% ± 58%, +59% ± 54%, and +42% ± 51%; group effect, P < 0.05). CONCLUSIONS Although obesity did not impair PEH after acute moderate-intensity exercise, young adults with obesity exhibited smaller postexercise peripheral vasodilation compared with young adults without obesity. Collectively, these findings have identified evidence for obesity-induced alterations in the peripheral vasculature after exercise.

Aging increases arterial stiffness, which has a negative impact on cerebral blood flow (CBF) regulation (decreases CBF and increases CBF pulsatility). The association between arterial stiffness and CBF pulsatility may, in part, explain the relationship between elevated blood pressure (BP) fluctuations and end-organ disease with aging. To understand the mechanisms by which large BP alterations influence cerebral blood flow regulation in both young and old, we examined the effects of age on central and cerebral blood flow regulation following an acute hypertensive stimulus [resistance-exercise (RE)]. Measurements were obtained pre and immediately, 5, and 30 min post-RE in young (n = 35) and older (n = 26) adults. Measurements included cerebral blood velocity (CBv), CBv pulsatility, central pulse-wave velocity (PWV), beta-stiffness index (β), and carotid blood flow pulsatility. Central hemodynamics and BP were continuously recorded. Mean CBv increased immediately post-RE only in the young and decreased below baseline at 5 min post-RE in both groups (interaction, P < 0.05). Older adults had a greater increase in CBv pulsatility immediately post-RE compared with the young (interaction, P < 0.05). Mean BP was higher and carotid pulsatility was lower in the older group and increased immediately post-RE in both groups (P < 0.05). PWV increased immediately post-RE (P < 0.05). There were no changes in β. In conclusion, with aging, greater central arterial stiffness leads to a greater transmission of pulsatile blood velocity from the systemic circulation to the cerebral circulation following an acute hypertensive stress.NEW & NOTEWORTHY Reductions in cerebral blood flow and increases in flow pulsatility with aging are associated to cerebrovascular disease; however, little is known about how an acute hypertensive stimulus effects cerebral blood flow regulation in an aged population. Following the hypertensive stimulus, older adults elicit an attenuated increase in cerebral blood velocity and greater transmission of pulsatile velocity to the brain compared with young adults, demonstrating reduced cerebral blood flow regulation to elevated blood pressure responses with aging.

Frequent consumption of high-fat meals and prolonged sedentary time are prevalent lifestyles that have been associated with an increased risk of vascular and metabolic complications. This study evaluated the acute effects of interrupting prolonged sitting with stair climbing on vascular and metabolic function after a high-fat meal. In a randomized, cross-over trial, 12 healthy adults (age: 23.5 ± 2.9 years) consumed a high-fat meal, followed by either 1) a 4-h uninterrupted sitting (sitting trial) or 2) a 4-h sitting interrupted with a 5-min stair climbing (average intensity: 66% of heart rate reserve) every hour (interrupted trial). Plasma triglyceride and glucose concentrations, as well as popliteal artery blood flow and shear rate were assessed at baseline and every hour after a high-fat meal, whereas brachial artery flow-mediated dilation was assessed at baseline and again at the end of each trial. Plasma triglyceride and glucose concentrations increased after a high-fat meal and returned to baseline at the end of both trials. Following a high-fat meal, brachial artery flow-mediated dilation decreased in the sitting trial, but not in the interrupted trial (sitting trial: 9.65 ± 2.63% to 7.84 ± 2.36%; interrupted trial: 9.41 ± 2.61% to 10.34 ± 3.30%, p = 0.009 for interaction). Compared with the sitting trial, the interrupted trial improved popliteal blood flow and shear rate (p = 0.004 and p = 0.008 for interaction, respectively). These findings suggest that interrupting prolonged sitting with stair climbing may be an effective lifestyle strategy to prevent against vascular dysfunction that might occur as a result of prolonged sitting after consuming a high-fat meal in young healthy adults.

The importance of nitric oxide (NO) in regulating cerebral blood flow (CBF) remains unresolved, due in part to methodological approaches, which lack comprehensive assessment of both global and regional effects. Importantly, NO synthase (NOS) expression and activity appear greater in some anterior brain regions, suggesting region-specific NOS influence on CBF. We hypothesized that NO contributes to basal CBF in healthy adults, in a regionally distinct pattern that predominates in the anterior circulation. 14 healthy adults (7 females; 24±5 years) underwent two magnetic resonance imaging (MRI) study visits with saline (placebo) or the NOS inhibitor, L-NMMA, administered in a randomized, single-blind approach. 4D Flow MRI quantified total and regional macrovascular CBF, whereas arterial spin labeling (ASL) MRI quantified total and regional microvascular perfusion. L-NMMA (or volume-matched saline) was infused intravenously for 5 minutes prior to imaging. L-NMMA reduced CBF (L-NMMA: 722±100 vs. placebo: 771±121 mL/min, p = 0.01) with similar relative reductions (5–7%) in anterior and posterior cerebral circulations, due in part to reduced cross sectional area of 9 of 11 large cerebral arteries. Global microvascular perfusion (ASL) was reduced by L-NMMA (L-NMMA: 42±7 vs. placebo: 47±8 mL/100g/min, p = 0.02), with 7–11% reductions in both hemispheres of frontal, parietal, and temporal lobes, and in the left occipital lobe. We conclude NO contributes to macrovascular and microvascular regulation including larger artery resting diameter. Contrary to our hypothesis, the influence of NO on cerebral perfusion appears regionally uniform in healthy young adults.

NEW FINDINGS: What is the central question of this study? Are central and peripheral haemodynamics during handgrip exercise different in young adults 3-4 weeks following infection with of SARS-CoV-2 compared with young healthy adults. What is the main finding and its importance? Exercising heart rate was higher while brachial artery blood flow and vascular conductance were lower in the SARS-CoV-2 compared with the control group. These findings provide evidence for peripheral impairments to exercise among adults with SARS-CoV-2, which may contribute to exercise limitations. ABSTRACT: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can have a profound impact on vascular function. While exercise intolerance may accompany a variety of symptoms associated with SARS-CoV-2 infection, the impact of SARS-CoV-2 on exercising blood flow (BF) remains unclear. Central (photoplethysmography) and peripheral (Doppler ultrasound) haemodynamics were determined at rest and during rhythmic handgrip (HG) exercise at 30% and 45% of maximal voluntary contraction (MVC) in young adults with mild symptoms 25 days after testing positive for SARS-CoV-2 (SARS-CoV-2: n = 8M/5F; age: 21 ± 2 years; height: 176 ± 11 cm; mass: 71 ± 11 kg) and were cross-sectionally compared with control subjects (Control: n = 8M/5F; age: 27 ± 6 years; height: 178 ± 8 cm; mass: 80 ± 25 kg). Systolic blood pressure, end systolic arterial pressure and rate pressure product were higher in the SARS-CoV-2 group during exercise at 45% MVC compared with controls. Brachial artery BF was lower in the SARS-CoV-2 group at both 30% MVC (Control: 384.8 ± 93.3 ml min-1 ; SARS-CoV-2: 307.8 ± 105.0 ml min-1 ; P = 0.041) and 45% MVC (Control: 507.4 ± 109.9 ml min-1 ; SARS-CoV-2: 386.3 ± 132.5 ml min-1 ; P = 0.002). Brachial artery vascular conductance was lower at both 30% MVC (Control: 3.93 ± 1.07 ml min-1 mmHg-1 ; SARS-CoV-2: 3.11 ± 0.98 ml min-1 mmHg-1 ; P = 0.022) and 45% MVC (Control: 4.74 ± 1.02 ml min-1 mmHg-1 ; SARS-CoV-2: 3.46 ± 1.10 ml min-1 mmHg-1 ; P

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.

Stair climbing is a form of physical activity that can be easily accessible in worksites and public settings, but it remains unclear whether stair climbing exercise is more effective in improving vascular health than walking exercise. The aim of this study was to compare the short-term effects of stair climbing exercise and walking exercise on vascular function in healthy young adults. Eighteen healthy adults were randomized to either the stair climbing exercise group (n=10) or the walking exercise group (n=8). The stair climbing exercise was performed inside a building, while the walking exercise involved a brisk walking exercise on the treadmill at the same exercise intensity (50-60% of heart rate reserve) for 2 weeks, 30 min/day, and 3 times/week. Peak oxygen uptake was measured by maximal cardiopulmonary exercise test. Carotid-femoral pulse wave velocity (c-f PWV) and flow-mediated dilation (FMD) as indexes of vascular function were measured using applanation tonometry and ultrasound machine, respectively. These variables were measured at baseline and again after 2 weeks of supervised exercise in both groups. FMD improved similarly in both groups (stair climbing: 11.5±2.2 to 14.3±2.4%, walking: 10.8±1.3 to 12.1±2.9%, time effect: p

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.

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.

Aims Although both low socioeconomic status (SES) and poor cardiorespiratory fitness (CRF) are associated with increased chronic disease and heightened mortality, it remains unclear whether moderate-to-high levels of CRF are associated with survival benefits in low SES populations. This study evaluated the hypothesis that SES and CRF predict all-cause mortality and cardiovascular disease mortality and that moderate-to-high levels of CRF may attenuate the association between low SES and increased mortality. Methods This study included 2368 men, who were followed in the Kuopio Ischaemic Heart Disease Study cohort. CRF was directly measured by peak oxygen uptake during progressive exercise testing. SES was characterized using self-reported questionnaires. Results During a 25-year median follow-up, 1116 all-cause mortality and 512 cardiovascular disease mortality events occurred. After adjusting for potential confounders, men with low SES were at increased risks for all-cause mortality (hazard ratio 1.49, 95% confidence interval: 1.30–1.71) and cardiovascular disease mortality (hazard ratio1.38, 1.13–1.69). Higher levels of CRF were associated with lower risks of all-cause mortality (hazard ratio 0.54, 0.45–0.64) and cardiovascular disease mortality (hazard ratio 0.53, 0.40–0.69). In joint associations of SES and CRF with mortality, low SES-unfit had significantly higher risks of all-cause mortality (hazard ratio 2.15, 1.78–2.59) and cardiovascular disease mortality (hazard ratio 1.95, 1.48-2.57), but low SES-fit was not associated with a heightened risk of cardiovascular disease mortality (hazard ratio 1.09, 0.80-1.48) as compared with their high SES-fit counterparts. Conclusion Both SES and CRF were independently associated with subsequent mortality; however, moderate-to-high levels of CRF were not associated with an excess risk of cardiovascular disease mortality in men with low SES.

The authors investigated the hypothesis that high serum uric acid concentrations may be related to an exaggerated systolic blood pressure (SBP) response to maximal exercise testing in men with normotension, independent of potential confounding variables. In 4640 healthy men with normotension who underwent maximal treadmill exercise testing and fasting blood chemistry studies, including serum uric acid concentrations, an exaggerated SBP response, defined as SBP ≥ 210 mm Hg, was detected in 152 men (3.3%). After adjusting for potential confounders, participants in the highest quartile of serum uric acid (>6.6 mg/dL) had a higher odds ratio of demonstrating an exaggerated SBP to maximal exercise (odds ratio, 2.19; 95% confidence interval, 1.24-3.86) compared with participants in the lowest quartile of serum uric acid (

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