Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation. METHODS: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO2) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO2, and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity. RESULTS: Peak VO2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P=0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO2/dL blood; P<0.001). During single leg knee extension, there was no difference in peak leg VO2 (P=0.306), but the peripherally limited group had greater blood flow/VO2 ratio (P=0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO2/dL blood; P=0.013), and lower muscle oxygen diffusive conductance (P=0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected (P=0.199). CONCLUSIONS: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O2 ratio and poor muscle diffusive capacity. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844.

Sympathetic transduction at rest and during cold pressor test in young healthy non-Hispanic Black and White women.

Non-Hispanic Black (BL) individuals have the highest prevalence of hypertension and cardiovascular disease (CVD) compared with all other racial/ethnic groups. Previous work focused on racial disparities in sympathetic control and blood pressure (BP) regulation between young BL and White (WH) adults, have mainly included men. Herein, we hypothesized that BL women would exhibit augmented resting sympathetic vascular transduction and greater sympathetic and BP reactivity to cold pressor test (CPT) compared with WH women. Twenty-eight young healthy women (BL: n = 14, 22 [Formula: see text] 4 yr; WH: n = 14, 22 [Formula: see text] 4 yr) participated. Beat-to-beat BP (Finometer), common femoral artery blood flow (duplex Doppler ultrasound), and muscle sympathetic nerve activity (MSNA; microneurography) were continuously recorded. In a subset (BL n = 10, WH n = 11), MSNA and BP were recorded at rest and during a 2-min CPT. Resting sympathetic vascular transduction was quantified as changes in leg vascular conductance (LVC) and mean arterial pressure (MAP) following spontaneous bursts of MSNA using signal averaging. Sympathetic and BP reactivity were quantified as changes in MSNA and MAP during the last minute of CPT. There were no differences in nadir LVC following resting MSNA bursts between BL (-8.70 ± 3.43%) and WH women (-7.30 ± 3.74%; P = 0.394). Likewise, peak increases in MAP following MSNA bursts were not different between groups (BL: +2.80 ± 1.42 mmHg; vs. WH: +2.99 ± 1.15 mmHg; P = 0.683). During CPT, increases in MSNA and MAP were also not different between BL and WH women, with similar transduction estimates between groups (ΔMAP/ΔMSNA; P = 0.182). These findings indicate that young, healthy BL women do not exhibit exaggerated sympathetic transduction or augmented sympathetic and BP reactivity during CPT.NEW & NOTEWORTHY This study was the first to comprehensively investigate sympathetic vascular transduction and sympathetic and BP reactivity during a cold pressor test in young, healthy BL women. We demonstrated that young BL women do not exhibit exaggerated resting sympathetic vascular transduction and do not have augmented sympathetic or BP reactivity during cold stress compared with their WH counterparts. Collectively, these findings suggest that alterations in sympathetic transduction and reactivity are not apparent in young, healthy BL women.

Cardiovascular and cerebral vascular health in females with postacute sequelae of COVID-19.

Many individuals who had coronavirus disease 2019 (COVID-19) develop detrimental persistent symptoms, a condition known as postacute sequelae of COVID-19 (PASC). Despite the elevated risk of cardiovascular disease following COVID-19, limited studies have examined vascular function in PASC with equivocal results reported. Moreover, the role of PASC symptom burden on vascular health has not been examined. We tested the hypothesis that peripheral and cerebral vascular function would be blunted and central arterial stiffness would be elevated in patients with PASC compared with age-matched controls. Furthermore, we hypothesized that impairments in vascular health would be greater in those with higher PASC symptom burden. Resting blood pressure (BP; brachial and central), brachial artery flow-mediated dilation (FMD), forearm reactive hyperemia, carotid-femoral pulse wave velocity (PWV), and cerebral vasodilator function were measured in 12 females with PASC and 11 age-matched female controls without PASC. The severity of persistent symptoms in those with PASC was reported on a scale of 1-10 (higher score: greater severity). Brachial BP (e.g., systolic BP, 126 ± 19 vs.109 ± 8 mmHg; P = 0.010), central BP (P < 0.050), and PWV (7.1 ± 1.2 vs. 6.0 ± 0.8 m/s; P = 0.015) were higher in PASC group compared with controls. However, FMD, reactive hyperemia, and cerebral vasodilator function were not different between groups (P > 0.050 for all). Total symptom burden was not correlated with any measure of cardiovascular health (P > 0.050 for all). Collectively, these findings indicate that BP and central arterial stiffness are elevated in females with PASC, whereas peripheral and cerebral vascular function appear to be unaffected, effects that appear independent of symptom burden.NEW & NOTEWORTHY We demonstrate for the first time that resting blood pressure (BP) and central arterial stiffness are higher in females with PASC compared with controls. In contrast, peripheral and cerebral vascular functions appear unaffected. Moreover, there was no relationship between total PASC symptom burden and measures of BP, arterial stiffness, or vascular function. Collectively, these findings suggest that females with PASC could be at greater risk of developing hypertension, which appears independent of symptom burden.

Impact of COVID-19 on cardiac autonomic function in healthy young adults: potential role of symptomatology and time since diagnosis.

Emerging evidence suggests that COVID-19 may affect cardiac autonomic function; however, the limited findings in young adults with COVID-19 have been equivocal. Notably, symptomology and time since diagnosis appear to influence vascular health following COVID-19, but this has not been explored in the context of cardiac autonomic regulation. Therefore, we hypothesized that young adults who had persistent symptoms following COVID-19 would have lower heart rate variability (HRV) and cardiac baroreflex sensitivity (BRS) compared with those who had COVID-19 but were asymptomatic at testing and controls who never had COVID-19. Furthermore, we hypothesized that there would be relationships between cardiac autonomic function measures and time since diagnosis. We studied 27 adults who had COVID-19 and were either asymptomatic (ASYM; n = 15, 6 females); 21 ± 4 yr; 8.4 ± 4.0 wk from diagnosis) or symptomatic (SYM; n = 12, 9 females); 24 ± 3 yr; 12.3 ± 6.2 wk from diagnosis) at testing, and 20 adults who reported never having COVID-19 (24 ± 4 yr, 11 females). Heart rate and beat-to-beat blood pressure were continuously recorded during 5 min of rest to assess HRV and cardiac BRS. HRV [root mean square of successive differences between normal heartbeats (RMSSD); control, 73 ± 50 ms; ASYM, 71 ± 47 ms; and SYM, 84 ± 45 ms; P = 0.774] and cardiac BRS (overall gain; control, 22.3 ± 10.1 ms/mmHg; ASYM, 22.7 ± 12.2 ms/mmHg; and SYM, 24.3 ± 10.8 ms/mmHg; P = 0.871) were not different between groups. However, we found correlations with time since diagnosis for HRV (e.g., RMSSD, r = 0.460, P = 0.016) and cardiac BRS (overall gain, r = 0.470, P = 0.014). These data suggest a transient impact of COVID-19 on cardiac autonomic function that appears mild and unrelated to persistent symptoms in young adults.NEW & NOTEWORTHY The potential role of persistent COVID-19 symptoms on cardiac autonomic function in young adults was investigated. We observed no differences in heart rate variability or cardiac baroreflex sensitivity between controls who never had COVID-19 and those who had COVID-19, regardless of symptomology. However, there were significant relationships between measures of cardiac autonomic function and time since diagnosis, suggesting that COVID-19-related changes in cardiac autonomic function are transient in young, otherwise healthy adults.

Impact of COVID-19 on ambulatory blood pressure in young adults: a cross-sectional analysis investigating time since diagnosis.

Previous studies have reported detrimental effects of COVID-19 on the peripheral vasculature. However, reports on blood pressure (BP) are inconsistent, and measurements are made only in the laboratory setting. To date, no studies have measured ambulatory BP. In addition, in previous studies, time since COVID-19 diagnosis among participants varied across a wide range, potentially contributing to the inconsistent BP results. Thus, we aimed to perform a comprehensive assessment of BP and BP variability using ambulatory and laboratory (brachial and central) measurements in young adults who had COVID-19. We hypothesized that ambulatory BP would be elevated post-COVID-19 and that measures of BP would be inversely related with time since diagnosis. Twenty-eight young adults who had COVID-19 [11 ± 6 (range 3-22) wk since diagnosis] and 10 controls were studied. Ambulatory daytime, nighttime, and 24-h systolic BP, diastolic BP, and mean BP were not different between the control and COVID groups (e.g., daytime systolic BP: control, 122 ± 12 mmHg; COVID, 122 ± 10 mmHg; P = 0.937). Similar results were observed for laboratory BPs (all P > 0.05). However, ambulatory daytime, nighttime, and 24-h BPs as well as laboratory brachial BPs were inversely correlated with time since COVID-19 diagnosis (e.g., daytime systolic BP: r = -0.444; P = 0.044, nighttime systolic BP: r = -0.518; P = 0.016). Ambulatory and laboratory-measured BP variability were not different between groups nor correlated with time since diagnosis. Collectively, these data suggest that adverse effects of COVID-19 on BP in young adults are minimal and likely transient.NEW & NOTEWORTHY We report for the first time that ambulatory daytime, nighttime, and 24-h blood pressure (BP), as well as laboratory BP, were not different between control and COVID participants. However, a significant inverse relationship with time since COVID-19 diagnosis was found (i.e., greater BP with more recent infection). Ambulatory and laboratory BP variability were unaffected and not related with diagnosis time. These findings suggest that COVID-19 may exert only short-lasting effects on BP in young adults.

Impact of breakthrough COVID-19 cases during the omicron wave on vascular health and cardiac autonomic function in young adults.

We and others have previously shown that COVID-19 results in vascular and autonomic impairments in young adults. However, the newest variant of COVID-19 (Omicron) appears to have less severe complications. Therefore, we investigated whether recent breakthrough infection with COVID-19 during the Omicron wave impacts cardiovascular health in young adults. We hypothesized that measures of vascular health and indices of cardiac autonomic function would be impaired in those who had the Omicron variant of COVID-19 when compared with controls who never had COVID-19. We studied 23 vaccinated adults who had COVID-19 after December 25, 2021 (Omicron; age, 23 ± 3 yr; 14 females) within 6 wk of diagnosis compared with 13 vaccinated adults who never had COVID-19 (age, 26 ± 4 yr; 7 females). Macro- and microvascular function were assessed using flow-mediated dilation (FMD) and reactive hyperemia, respectively. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cfPWV) and augmentation index (AIx). Heart rate (HR) variability and cardiac baroreflex sensitivity (BRS) were assessed as indices of cardiac autonomic function. FMD was not different between control (5.9 ± 2.8%) and Omicron (6.1 ± 2.3%; P = 0.544). Similarly, reactive hyperemia (P = 0.884) and arterial stiffness were not different between groups (e.g., cfPWV; control, 5.9 ± 0.6 m/s and Omicron, 5.7 ± 0.8 m/s; P = 0.367). Finally, measures of HR variability and cardiac BRS were not different between groups (all, P > 0.05). Collectively, these data suggest preserved vascular health and cardiac autonomic function in young, otherwise healthy adults who had breakthrough cases of COVID-19 during the Omicron wave.NEW & NOTEWORTHY We show for the first time that breakthrough cases of COVID-19 during the Omicron wave does not impact vascular health and cardiac autonomic function in young adults. These are promising results considering earlier research showing impaired vascular and autonomic function following previous variants of COVID-19. Collectively, these data demonstrate that the recent Omicron variant is not detrimental to cardiovascular health in young, otherwise healthy, vaccinated adults.

Blunted peripheral but not cerebral vasodilator function in young otherwise healthy adults with persistent symptoms following COVID-19.

Recent findings suggest that COVID-19 causes vascular dysfunction during the acute phase of the illness in otherwise healthy young adults. To date, to our knowledge, no studies have investigated the longer-term effects of COVID-19 on vascular function. Herein, we hypothesized that young, otherwise healthy adults who are past the acute phase of COVID-19 would exhibit blunted peripheral [brachial artery flow-mediated dilation (FMD) and reactive hyperemia] and cerebral vasodilator function (cerebral vasomotor reactivity to hypercapnia; CVMR) and increased central arterial stiffness. Sixteen young adults who were at least 4 wk past a COVID-19 diagnosis and 12 controls who never had COVID-19 were studied. Eight subjects with COVID-19 were symptomatic (SYM) and eight were asymptomatic (ASYM) at the time of testing. FMD and reactive hyperemia were not different between COVID and control groups. However, FMD was lower in SYM (3.8 ± 0.6%) compared with ASYM (6.8 ± 0.9%; P = 0.007) and control (6.8 ± 0.6%; P = 0.003) with no difference between ASYM and control. Similarly, peak blood velocity following cuff release was lower in SYM (47 ± 8 cm/s) compared with ASYM (64 ± 19 cm/s; P = 0.025) and control (61 ± 14 cm/s; P = 0.036). CVMR and arterial stiffness were not different between any groups. In summary, peripheral macrovascular and microvascular function, but not cerebral vascular function or central arterial stiffness were blunted in young adults symptomatic beyond the acute phase of COVID-19. In contrast, those who were asymptomatic had similar vascular function compared with controls who never had COVID-19.NEW & NOTEWORTHY This study was the first to investigate the persistent effects of COVID-19 on vascular function in otherwise healthy young adults. We demonstrated that peripheral macrovascular and microvascular vasodilation was significantly blunted in young adults still symptomatic from COVID-19 beyond the acute phase (>4 wk from diagnosis), whereas those who become asymptomatic have similar vascular function compared with controls who never had COVID-19. In contrast, cerebral vascular function and central arterial stiffness were unaffected irrespective of COVID-19 symptomology.

Attenuated Rapid-Onset Vasodilation to Forearm Muscle Contraction in Black Men.

PURPOSE: Non-Hispanic Black individuals have a blunted ability to vasodilate at rest compared with other racial groups. Limited studies have investigated blood flow responses to exercise in Black individuals. Recently, our laboratory demonstrated that Black men exhibit attenuated increases in forearm vascular conductance (FVC) during steady-state rhythmic handgrip. The mechanisms for this remain unknown. Herein, we used single muscle contractions, a modality that allows for assessment of rapid-onset vasodilation (ROV) independent of major elevations in shear stress, tissue metabolism, and systemic hemodynamics. METHODS: Ten young, healthy Black and White men performed single forearm contractions at 20%, 40%, and 60% maximal voluntary contraction (MVC). In addition, cuff inflations were performed on the forearm to examine the contribution of mechanical compression to ROV. Forearm blood flow (FBF; duplex Doppler ultrasound), heart rate (ECG), and mean arterial pressure (Finometer) were continuously measured. FVC was calculated as FBF/mean arterial pressure. RESULTS: Baseline FVC (White men vs Black men, 0.75 ± 0.11 vs 0.80 ± 0.09 mL·min-1·mm Hg-1; P = 0.73), FBF, and MVCs (White men vs Black men, 54 ± 2 vs 54 ± 2 kg; P = 0.95) were similar between the groups. After single contractions, both groups exhibited intensity-dependent FVC and FBF increases during ROV; however, these responses were attenuated in the Black group at all intensities (e.g., 60%MVC FVC: White men vs Black men, +371% ± 37% vs +220% ± 23% baseline; P = 0.001). FVC and FBF responses to cuff inflation alone were also attenuated in Black individuals (P < 0.001). CONCLUSIONS: Collectively, these data indicate that Black men have an overall blunted ability to rapidly vasodilate compared with young White men.

Functional sympatholysis is preserved in healthy young Black men during rhythmic handgrip exercise.

Black men have attenuated increases in forearm vascular conductance (FVC) and forearm blood flow (FBF) during moderate- and high-intensity rhythmic handgrip exercise compared with White men, but the underlying mechanisms are unclear. Here, we tested for the first time the hypothesis that functional sympatholysis (i.e., attenuation of sympathetic vasoconstriction in the exercising muscles) is impaired in Black men compared with White men. Thirteen White and 14 Black healthy young men were studied. FBF (duplex Doppler ultrasound) and mean arterial pressure (MAP; Finometer) were measured at rest and during rhythmic handgrip exercise at 30% maximal voluntary contraction. FVC was calculated as FBF/MAP. Sympathetic activation was induced via lower body negative pressure (LBNP) at -20 Torr for 2 min at rest and from the 3rd to the 5th min of handgrip. Sympathetic vasoconstriction was assessed as percent reductions in FVC during LBNP. The groups presented similar resting FVC, FBF, and MAP. During LBNP at rest, reductions in FVC were not different between White (-35 ± 10%) and Black men (-32 ± 14%, P = 0.616), indicating similar reflex-induced sympathetic vasoconstriction. During handgrip exercise, there were minimal reductions in FVC with LBNP in either group (White: -1 ± 7%; Black: +1 ± 8%; P = 0.523), indicating functional sympatholysis in both groups. Thus, contrary to our hypothesis, our findings indicate a preserved functional sympatholysis in healthy young Black men compared with White men, suggesting that this mechanism does not appear to contribute to reduced exercise hyperemia during moderate-intensity rhythmic handgrip in this population.

Muscle pump-induced inhibition of sympathetic vasomotor outflow during low-intensity leg cycling is attenuated by muscle metaboreflex activation.

Muscle sympathetic nerve activity (MSNA) decreases during leg cycling at low intensity because of muscle pump-induced increases in venous return and loading of the cardiopulmonary baroreceptors. However, MSNA increases during leg cycling when exercise is above moderate intensity or for a long duration, suggesting that the sympathoinhibitory effect of the cardiopulmonary baroreflex can be overridden by a powerful sympathoexcitatory drive, such as the skeletal muscle metaboreflex. Therefore, we tested the hypothesis that high-intensity muscle metaboreflex activation attenuates muscle pump-induced inhibition of MSNA during leg cycling. MSNA (left radial nerve) was recorded during graded isolation of the muscle metaboreflex in the forearm with postexercise ischemia (PEI) after low (PEI-L)- and high (PEI-H)-intensity isometric handgrip exercise (20% and 40% maximum voluntary contraction, respectively). Leg cycling (15-20 W) was performed alone and during each PEI trial (PEI-L+Cycling, PEI-H+Cycling). Cycling alone induced a significant decrease in MSNA burst frequency (BF) and total activity (TA). MSNA BF and TA also decreased when cycling was performed during PEI-L. However, the magnitude of decrease in MSNA during PEI-L+Cycling [∆BF: -19 ± 2% (P < 0.001), ∆TA: -25 ± 4% (P < 0.001); mean ± SE] was less than that during cycling alone [∆BF: -39 ± 5% (P = 0.003), ∆TA: -45 ± 5% (P = 0.002)]. More importantly, MSNA did not decrease during cycling with PEI-H [∆BF: -1 ± 2% (P = 0.845), ∆TA: +2 ± 3% (P = 0.959)]. These results suggest that muscle pump-induced inhibition of sympathetic vasomotor outflow during low-intensity leg cycling is attenuated by muscle metaboreflex activation in an intensity-dependent manner.NEW & NOTEWORTHY There are no available data concerning the interaction between the sympathoinhibitory effect of muscle pump-induced cardiopulmonary baroreflex loading during leg cycling and the sympathoexcitatory influence of the muscle metaboreflex. In this study, muscle metaboreflex activation attenuated the inhibition of muscle sympathetic nerve activity (MSNA) during leg cycling. This may explain, in part, the response of MSNA to graded-intensity dynamic exercise in which low-intensity leg cycling inhibits MSNA whereas high-intensity exercise elicits graded sympathoexcitation.