Statin administration improves vascular function in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired vascular endothelial function that may be improved by hydroxy-methylglutaryl-CoA (HMG-CoA) reductase enzyme inhibition. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on peripheral vascular function and biomarkers of inflammation and oxidative stress in 16 patients with HFpEF [Statin: n = 8, 74 ± 6 yr, ejection fraction (EF) 52-73%; Placebo: n = 8, 67 ± 9 yr, EF 56-72%]. Flow-mediated dilation (FMD) and sustained-stimulus FMD (SS-FMD) during handgrip (HG) exercise, reactive hyperemia (RH), and blood flow during HG exercise were evaluated to assess conduit vessel function, microvascular function, and exercising muscle blood flow, respectively. FMD improved following statin administration (pre, 3.33 ± 2.13%; post, 5.23 ± 1.35%; P < 0.01), but was unchanged in the placebo group. Likewise, SS-FMD, quantified using the slope of changes in brachial artery diameter in response to increases in shear rate, improved following statin administration (pre: 5.31e-5 ± 3.85e-5 mm/s-1; post: 8.54e-5 ± 4.98e-5 mm/s-1; P = 0.03), with no change in the placebo group. Reactive hyperemia and exercise hyperemia responses were unchanged in both statin and placebo groups. Statin administration decreased markers of lipid peroxidation (malondialdehyde, MDA) (pre, 0.652 ± 0.095; post, 0.501 ± 0.094; P = 0.04), whereas other inflammatory and oxidative stress biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve brachial artery endothelium-dependent vasodilation, but not microvascular function or exercising limb blood flow, in patients with HFpEF, which may be due in part to reductions in oxidative stress.NEW & NOTEWORTHY This is the first study to investigate the impact of statin administration on vascular function and exercise hyperemia in patients with heart failure with preserved ejection fraction (HFpEF). In support of our hypothesis, both conventional flow-mediated dilation (FMD) testing and brachial artery vasodilation in response to sustained elevations in shear rate during handgrip exercise increased significantly in patients with HFpEF following statin administration, beneficial effects that were accompanied by a decrease in biomarkers of oxidative damage. However, contrary to our hypothesis, reactive hyperemia and exercise hyperemia were unchanged in patients with HFpEF following statin therapy. These data provide new evidence for the efficacy of low-dose statin administration to improve brachial artery endothelium-dependent vasodilation, but not microvascular reactivity or exercising muscle blood flow in patients with HFpEF, which may be due in part to reductions in oxidative stress.

Impaired cardiopulmonary baroreflex function and altered cardiovascular responses to hypovolemia in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is associated with autonomic dysregulation, which may be related to baroreflex dysfunction. Thus, we tested the hypothesis that cardiac and peripheral vascular responses to baroreflex activation via lower-body negative pressure (LBNP; -10, -20, -30, -40 mmHg) would be diminished in patients with HFpEF (n = 10, 71 ± 7 yr) compared with healthy controls (CON, n = 9, 69 ± 5 yr). Changes in heart rate (HR), mean arterial pressure (MAP, Finapres), forearm blood flow (FBF, ultrasound Doppler), and thoracic impedance (Z) were determined. Mild levels of LBNP (-10 and -20 mmHg) were used to specifically assess the cardiopulmonary baroreflex, whereas responses across the greater levels of LBNP represented an integrated baroreflex response. LBNP significantly increased in HR in CON subjects at -30 and -40 mmHg (+3 ± 3 and +6 ± 5 beats/min, P < 0.01), but was unchanged in patients with HFpEF across all LBNP levels. LBNP provoked progressive peripheral vasoconstriction, as quantified by changes in forearm vascular conductance (FVC), in both groups. However, a marked (40%-60%) attenuation in FVC responses was observed in patients with HFpEF (-6 ± 8, -15 ± 6, -16 ± 5, and -19 ± 7 mL/min/mmHg at -10, -20, -30, and -40 mmHg, respectively) compared with controls (-15 ± 10, -22 ± 6, -25 ± 10, and -28 ± 10 mL/min/mmHg, P < 0.01). MAP was unchanged in both groups. Together, these data provide new evidence for impairments in cardiopulmonary baroreflex function and diminished cardiovascular responsiveness during hypovolemia in patients with HFpEF, which may be an important aspect of the disease-related changes in autonomic cardiovascular control in this patient group.NEW & NOTEWORTHY Data from the current study demonstrate diminished cardiovascular responsiveness during hypovolemia induced by incremental lower-body negative pressure in patients with heart failure with preserved ejection fraction (HFpEF). These diminished responses imply impaired cardiopulmonary baroreflex function and altered autonomic cardiovascular regulation which may represent an important aspect of HFpEF pathophysiology.

Exercise intolerance in heart failure with preserved ejection fraction: Causes, consequences and the journey towards a cure.

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases nationwide and continues to rise in its prevalence. The complex, multi-organ involvement of the HFpEF clinical syndrome requires clinicians and investigators to adopt an integrative approach that considers the contribution of both cardiac and non-cardiac function to HFpEF pathophysiology. Thus, this symposium review outlines the key points from presentations covering the contributions of disease-related changes in cardiac function, arterial stiffness, peripheral vascular function, and oxygen delivery and utilization to exercise tolerance in patients with HFpEF. While many aspects of HFpEF pathophysiology remain poorly understood, there is accumulating evidence for a decline in vascular health in this patient group that may be remediable through pharmacological and lifestyle interventions and could improve outcomes and clinical status in this ever-growing patient population.

Interplay of Race and Neighborhood Deprivation on Ambulatory Blood Pressure in Young Adults.

Background: Ambulatory blood pressure (BP) monitoring measures nighttime BP and BP dipping, which are superior to in-clinic BP for predicting cardiovascular disease (CVD), the leading cause of death in America. Compared with other racial/ethnic groups, Black Americans exhibit elevated nighttime BP and attenuated BP dipping, including in young adulthood. Social determinants of health contribute to disparities in CVD risk, but the contribution of neighborhood deprivation on nighttime BP is unclear. Therefore, we examined associations between neighborhood deprivation with nighttime BP and BP dipping in young Black and White adults. Methods: We recruited 21 Black and 26 White participants (20 M/27 F, mean age: 21 years, body mass index: 25±4 kg/m2) for 24-hour ambulatory BP monitoring. We assessed nighttime BP and BP dipping (nighttime:daytime BP ratio). The area deprivation index (ADI) was used to measure neighborhood deprivation. Associations between ADI and ambulatory BP were examined. Results: Black participants exhibited higher nighttime diastolic BP compared with White participants (63±8 mmHg vs 58±7 mmHg, p=0.003), and attenuated BP dipping ratios for both systolic (0.92±0.06 vs 0.86±0.05, p=0.001) and diastolic BP (0.86±0.09 vs 0.78±0.08, p=0.007). Black participants experienced greater neighborhood deprivation compared with White participants (ADI scores: 110±8 vs 97±21, p<0.001), and ADI was associated with attenuated systolic BP dipping (ρ=0.342, p=0.019). Conclusions: Our findings suggest neighborhood deprivation may contribute to higher nighttime BP and attenuated BP dipping, which are prognostic of CVD, and more prevalent in Black adults. Targeted interventions to mitigate the effects of neighborhood deprivation may help to improve nighttime BP. Clinical Trial Registry: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04576338.

Neural control of the circulation during exercise in heart failure with reduced and preserved ejection fraction.

Patients with heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) exhibit severe exercise intolerance that may be due, in part, to inappropriate cardiovascular and hemodynamic adjustments to exercise. Several neural mechanisms and locally released vasoactive substances work in concert through complex interactions to ensure proper adjustments to meet the metabolic demands of the contracting skeletal muscle. Specifically, accumulating evidence suggests that disease-related alterations in neural mechanisms (e.g., central command, exercise pressor reflex, arterial baroreflex, and cardiopulmonary baroreflex) contribute to heightened sympathetic activation and impaired ability to attenuate sympathetic vasoconstrictor responsiveness that may contribute to reduced skeletal muscle blood flow and severe exercise intolerance in patients with HFrEF. In contrast, little is known regarding these important aspects of physiology in patients with HFpEF, though emerging data reveal heightened sympathetic activation and attenuated skeletal muscle blood flow during exercise in this patient population that may be attributable to dysregulated neural control of the circulation. The overall goal of this review is to provide a brief overview of the current understanding of disease-related alterations in the integrative neural cardiovascular responses to exercise in both HFrEF and HFpEF phenotypes, with a focus on sympathetic nervous system regulation during exercise.

Evidence of impaired functional sympatholysis in patients with heart failure with preserved ejection fraction.

Exercising muscle blood flow is reduced in patients with heart failure with a preserved ejection fraction (HFpEF), which may be related to disease-related changes in the ability to overcome sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, (i.e., "functional sympatholysis"). Thus, in 12 patients with HFpEF (69 ± 7 yr) and 11 healthy controls (Con, 69 ± 4 yr), we examined forearm blood flow (FBF), mean arterial pressure (MAP), and forearm vascular conductance (FVC) during rhythmic handgrip exercise (HG) at 30% of maximum voluntary contraction with or without lower-body negative pressure (LBNP, -20 mmHg) to increase SNS activity and elicit peripheral vasoconstriction. SNS-mediated vasoconstrictor responses were determined as LBNP-induced changes (%Δ) in FVC, and the "magnitude of sympatholysis" was calculated as the difference between responses at rest and during exercise. At rest, the LBNP-induced change in FVC was significantly lesser in HFpEF compared with Con (HFpEF: -9.5 ± 5.5 vs. Con: -21.0 ± 8.0%; P < 0.01). During exercise, LBNP-induced %ΔFVC was significantly attenuated in Con compared with rest (HG: -5.8 ± 6.0%; P < 0.05) but not in HFpEF (HG: -9.9 ± 2.5%; P = 0.88). Thus, the magnitude of sympatholysis was lesser in HFpEF compared with Con (HFpEF: 0.4 ± 4.7 vs. Con: -15.2 ± 11.8%; P < 0.01). These data demonstrate a diminished ability to attenuate SNS-mediated vasoconstriction in HFpEF and provide new evidence suggesting impaired functional sympatholysis in this patient group.NEW & NOTEWORTHY Data from the current study suggest that functional sympatholysis, or the ability to adequately attenuate sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, is impaired in patients with heart failure with preserved ejection fraction (HFpEF). These observations extend the current understanding of HFpEF pathophysiology by implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

Autonomic cardiovascular control during exercise.

The cardiovascular response to exercise is largely determined by neurocirculatory control mechanisms that help to raise blood pressure and modulate vascular resistance which, in concert with regional vasodilatory mechanisms, promote blood flow to active muscle and organs. These neurocirculatory control mechanisms include a feedforward mechanism, known as central command, and three feedback mechanisms, namely, 1) the baroreflex, 2) the exercise pressor reflex, and 3) the arterial chemoreflex. The hemodynamic consequences of these control mechanisms result from their influence on the autonomic nervous system and subsequent alterations in cardiac output and vascular resistance. Although stimulation of the baroreflex inhibits sympathetic outflow and facilitates parasympathetic activity, central command, the exercise pressor reflex, and the arterial chemoreflex facilitate sympathetic activation and inhibit parasympathetic drive. Despite considerable understanding of the cardiovascular consequences of each of these mechanisms in isolation, the circulatory impact of their interaction, which occurs when various control systems are simultaneously activated (e.g., during exercise at altitude), has only recently been recognized. Although aging and cardiovascular disease (e.g., heart failure, hypertension) have both been recognized to alter the hemodynamic consequences of these regulatory systems, this review is limited to provide a brief overview on the action and interaction of neurocirculatory control mechanisms in health.

Cardiovascular responses to static handgrip exercise and postexercise ischemia in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterized by reduced ability to sustain physical activity that may be due partly to disease-related changes in autonomic function that contribute to dysregulated cardiovascular control during muscular contraction. Thus, we used a combination of static handgrip exercise (HG) and postexercise 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 16 patients with HFpEF and 17 healthy, similarly aged controls. Changes in MAP were lower in patients with HFpEF compared with 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 = 0.078 and P = 0.017 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 with similarly aged controls that may be mediated partly by a blunted muscle metaboreflex. These findings support a disease-related dysregulation in neural cardiovascular control that may reduce an ability to sustain physical activity in HFpEF.NEW & NOTEWORTHY The current investigation has identified a diminution in the exercise-induced rise in arterial blood pressure (BP) that persisted during postexercise ischemia (PEI) in an intensity-dependent manner in patients with heart failure with preserved ejection fraction (HFpEF) compared with older, healthy controls. These findings suggest that the pressor response to exercise is reduced in patients with HFpEF, and this deficit may be mediated, in part, by a blunted muscle metaboreflex, highlighting the consequences of impaired neural cardiovascular control during exercise in this patient group.

Associations of Cardiorespiratory Fitness With Estimated Remnant Cholesterol and Non-High-Density Lipoprotein Cholesterol in Healthy Men.

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 (ß -0.31, 95% confidence interval [CI] -0.39 to -0.24) and non-HDL-C (ß -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.

Improved vascular function and functional capacity following l-citrulline administration in patients with heart failure with preserved ejection fraction: a single-arm, open-label, prospective pilot study.

There is accumulating evidence for both peripheral vascular dysfunction and impaired functional capacity in patients with heart failure with a preserved ejection fraction (HFpEF). Although 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, 6 g/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 [6-min walk test (6MWT)], and biomarkers of l-Arg-NO signaling in 14 patients with HFpEF (n = 14, 4 M/10 F, 70 ± 10 yr, EF: 66 ± 7%). Compared with baseline (0d), 7 days of l-Cit administration improved FMD (0d: 2.5 ± 1.6%, 7d: 4.5 ± 2.9%), RH (0d: 468 ± 167 mL, 7d: 577 ± 199 mL), PLM blood flow area-under-the-curve (0d: 139 ± 130 mL, 7d: 198 ± 115 mL), and 6MWT distance (0d: 377 ± 27 m, 7d: 397 ± 27 m) (P < 0.05). An increase in plasma l-Cit (0d: 42 ± 11 µM/L, 7d: 369 ± 201 µM/L), l-Arg (0d: 65 ± 8 µM/L, 7d: 257 ± 25 µM/L), and the ratio of l-Arg to asymmetric dimethylarginine (ADMA) (0d: 136 ± 13 AU, 7d: 481 ± 49 AU) (P < 0.05) 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.NEW & NOTEWORTHY 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.

Separate and Joint Associations of Cardiorespiratory Fitness and Healthy Vascular Aging With Subclinical Atherosclerosis in 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 <140/90 mm Hg without hypertension and brachial-ankle pulse wave velocity <1266 cm/s. CRF was directly measured by peak oxygen uptake. Subclinical atherosclerosis was defined as coronary artery calcification scores of >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.

Racial and ethnic disparities in cardiometabolic disease and COVID-19 outcomes in White, Black/African American, and Latinx populations: Social determinants of health.

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.

Racial and ethnic disparities in cardiometabolic disease and COVID-19 outcomes in White, Black/African American, and Latinx populations: Physiological underpinnings.

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.

Comparison of the acute effects of ankle bathing versus moderate-intensity aerobic exercise on vascular function in young adults.

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), ß-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 ß-stiffness index and arterial compliance, while AB reduced ß-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.

The impact of obesity on the regulation of muscle blood flow during exercise in patients with heart failure with a preserved ejection fraction.

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/m2, n = 14) and obese (BMI > 30 kg/m2, 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.

Altered central and peripheral haemodynamics during rhythmic handgrip exercise in young adults with SARS-CoV-2.

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 < 0.001) in the SARS-CoV-2 group compared to control group. The shear-induced dilatation of the brachial artery increased similarly across exercise intensities in the two groups, suggesting the decrease in exercising BF may be due to microvascular impairments. Brachial artery BF is attenuated during HG exercise in young adults recently diagnosed with mild SARS-CoV-2, which may contribute to diminished exercise capacity among those recovering from SARS-CoV-2 like that seen in severe cases.

When it's time for the sex talk, words matter.

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.