Citations

Recent research focuses on the cerebrovascular response to vasodilatory stimuli as an index of cerebrovascular health; however, vasoconstrictor responses in the brain are likely equally important. We previously have shown that cerebral vasoconstrictor responses to hypocapnia are not affected by aging; however, this was evaluated in primarily sedentary adults. Therefore, we hypothesized that middle cerebral artery velocity (MCAv) vasoconstrictor responses to hypocapnia are dependent on age and habitual physical activity. We evaluated 13 young physically active (YA; age = 30±5 y; VO 2 max = 45±8 mL/kg/min), 6 young sedentary (YS; age = 29±4 y; VO 2 max = 26±3 mL/kg/min), 10 older physically active (OA; age= 61±6 y; VO 2 max =35±7 mL/kg/min) and 8 older sedentary (OS; age = 65±8 y; VO 2 max 23±2 mL/kg/min) adults during the recovery from inhaled 6% CO 2 to room air. Mean arterial pressure (MAP) end tidal CO 2 (ETCO 2 ) and MCAv were recorded throughout. Using a breath‐by breath analysis, cerebrovascular conductance index (CVCi=MCAv/MAP) reactivity was calculated as a slope of CVCi and ETCO 2 and used to quantify vasoconstrictor responses. CVCi reactivity was higher in YA adults (slope=2.74±0.9 AU) compared with both YS (slope=2.20±1.1 AU) and older groups (OA: slope=2.08±0.5 AU; OS: slope=2.07±0.7 AU; p<0.05 for all). There were no significant differences in CVCi reactivity between YS and either OA or OS (p=0.94, p=0.99 respectively). Additionally, CVCi negatively correlated with age (r=−0.38, p<0.05). Our results indicate that aging attenuates the cerebral vasoconstrictor response to hypocapnia in older adults in comparison to physically‐active young adults, but not compared to sedentary young controls. A sedentary lifestyle resulted in attenuated vasoconstrictor responses in the young sedentary group, as their responses were not different than the older adults. It remains unclear how habitual physical activity preserves the cerebral vasoconstrictor response to hypocapnia in young people, and if a structured exercise training intervention would impact this response in older adults. Support or Funding Information NIH HL118154

Background Individuals with sleep apnea experience repeated intermittent hypoxic exposures during sleep. Previous work in sleep apnea showed patients have an increased heart rate (HR), corrected QT interval (QTc), QTc dispersion and P‐wave maximum duration and dispersion (max‐min P‐wave duration). Such changes have been linked to increased risk of cardiovascular disease and sudden cardiac death. Unfortunately, the mechanisms contributing to these changes are not completely understood. Given that individuals with sleep apnea experience repeated intermittent hypoxic exposures during sleep, we tested the hypothesis that exposure to intermittent hypoxia (IH) in young healthy adults would result in similar ECG changes to those seen in patients with sleep apnea. Methods To test this hypothesis, we completed ECG analysis of 7 healthy humans (6M/1F, Age=29±5 years, BMI=24±4kg/m 2 ) without sleep apnea before and after 3‐hours of exposure to IH. Subjects were exposed to hypoxic gas (0.05 FiO2) for 25‐seconds separated by 2‐minutes of room air breathing. This resulted in 25 hypoxic events per hour in which oxygen saturation was significantly reduced (Normoxia: 97%, Hypoxia: 89%, p<0.01). ECG analysis was completed in Lab Chart 7 software and consisted of measurement of intervals (RR, PR, QT), durations (P, QRS), and amplitudes (P, Q, R, S, T) during 10 minutes of normoxic quiet rest before and after IH exposure. QTc was calculated using Bazett's formula (QT duration/√HR). Dispersion of QTc and P waves were calculated as max duration ‐min duration. Results HR was significantly increased following IH (60±8 vs. 66±8 beats/min, baseline vs. post‐IH, respectively, p<0.05). There was no significant change in P‐wave maximum duration or dispersion following IH. QT interval was significantly decreased and QTc was significantly increased following IH (QT interval: 377±13 vs. 368±8ms, QTc: 377±22 vs 384±22ms, baseline vs. post‐IH, p<0.05 for both). QTc dispersion was not significantly different from baseline following IH. Conclusions We found that 3 hours of experimentally‐induced IH in young healthy individuals resulted in increased HR, decreased QT interval, and increased QTc. These data suggest that IH exposure experienced by patients with sleep apnea may contribute to ECG changes commonly observed in this population and subsequent increases in cardiovascular morbidity and mortality. Support or Funding Information Funding : DK90541 (MJJ), HL120570 (JKL)

Background We have previously shown that the carotid body chemoreceptors play an important role in glucoregulation. When the carotid bodies are experimentally desensitized in humans, counterregulatory responses to hypoglycemia are attenuated. Whether carotid body activation conversely increases circulating glucose levels was previously unexamined. We hypothesize plasma glucose levels would be increased in young healthy adults after carotid body activation via acute intermittent hypoxia. Methods Seven (6M/1F, 21–34 years) healthy, non‐obese, non‐diabetic, subjects without sleep apnea completed 2 visits randomized to 3‐hours of intermittent hypoxia or continuous normoxia. Oxygen saturation and ventilation (turbine ventilation flow transducer) were measured continuously. Plasma glucose levels and carotid body chemosensitivity (hypoxic ventilatory response, HVR) were measured before and after the 3‐hour protocol. Intermittent hypoxia consisted of 25‐s exposures to hypoxic gas (0.05 FiO 2 ) separated by 2‐min of room air breathing, resulting in 25‐events per hour in which oxygen saturation was significantly reduced (Normoxia: 97%, Hypoxia: 89%, p<0.01). Results No changes in plasma glucose (93 vs 93 mg/dL, p=0.92) or HVR (−0.35 vs. −0.39 L/min/%SpO 2, p=0.56) were observed after 3‐hours of continuous normoxia. In contrast, circulating glucose levels and chemosensitivity increased after intermittent hypoxia when compared to baseline (92 vs 97 mg/dL, p<0.01) and (−0.39 vs −0.60 L/min/%SpO 2 , p=0.04), respectively. Additionally, the rise in glucose was significantly correlated with the rise in carotid body chemosensitivity (R=0.38, p=0.05). Conclusion Circulating glucose levels increased after 3‐hours of intermittent hypoxia. The significant relationship between HVR and circulating glucose suggests that the carotid bodies may play a role in altered glucose handling. These findings may have important implications for the high prevalence of diabetes in patients with sleep apnea. Support or Funding Information DK90541, HL120570

Women who have experienced hypertensive pregnancy disorders (HPD) are at an increased risk for developing cardiovascular disease later in life, including fatal and non‐fatal stroke. Cerebrovascular reactivity is related to stroke in individuals with carotid artery disease, and it is possible that this measure may be altered in women with a history of HPD prior to overt cerebrovascular disease. It is unknown if cerebrovascular reactivity is altered in postmenopausal women decades after experiencing a hypertensive pregnancy. Therefore, the goal of this study was to determine if cerebral blood flow velocity and cerebrovascular reactivity are altered in women with a history of HPD in comparison to women with no history of HPD. We studied a cohort of postmenopausal women approximately 35 years after they experienced an HPD (n=27, age at testing: 58±1) and a group of age‐ and parity‐matched women with no history of HPD (n=30, age at testing: 59±1). We measured middle cerebral artery velocity (MCAv, via transcranial Doppler), continuous blood pressure (finger photoplethysmography), and end‐tidal CO 2 (nasal cannula) in these women at baseline (room air) and during stepped hypercapnia at 2, 4, and 6% inhaled CO 2 for 3 minutes at each condition. Women with a history of HPD had a higher body mass index than women without a history of HPD (29±1 vs. 26±1 kg/m 2 , respectively; p<0.05). At baseline and during 6% CO 2 , MCAv was lower in women with a history of HPD (baseline: 60±4 vs. 71±3 cm/s, respectively; 6% CO 2 : 82±6 vs. 99±5 cm/s, respectively; p<0.05 for both conditions) compared to women without a history of HPD. Cerebrovascular reactivity, the slope defining the association between MCAv and end‐tidal CO 2 across the entire breathing trial, was also lower in women with a history of HPD (2.0±0.2 vs. 2.7±0.2 cm/s/mmHg, respectively; p<0.05). Body mass index was not correlated with MCAv or cerebrovascular reactivity in either group (p>0.05). In conclusion, resting MCAv and cerebrovascular reactivity to CO 2 is lower in women with a history of HPD in comparison with women who have never experienced HPD. Our findings suggest that HPD may have long‐term effects on cerebrovascular regulation in women who have suffered from these conditions. Support or Funding Information NIH HL083947, NIA 1P50AG044170‐01, and CTSA UL1TR000135

Substantial evidence indicates that red blood cells (RBCs) can act as a ‘sensor’ for oxygen demand in addition to their traditional role as an oxygen ‘carrier’, in that they are able to stimulate vasodilation and increase oxygen delivery to the tissue through the release of ATP in direct proportion to the degree of hemoglobin (Hb) deoxygenation. However, RBCs from older adults have an impaired ability to release ATP in response to Hb deoxygenation compared to RBCs from young adults, yet the underlying cause of this remains unknown. RBC membrane deformability has been shown to decrease with advancing donor age, thus we hypothesized that increasing membrane deformability (via the Rho‐kinase inhibitor Y‐27632) would restore ATP release from RBCs of older adults, while decreasing membrane deformability (via the cell‐stiffening agent diamide) would impair ATP release from RBCs of young adults. Isolated RBC ATP release in response to normoxic (PO 2 ~110 mmHg) and hypoxic (PO 2 ~20 mmHg) stimuli was quantified in RBCs from young (23 ± 3 years; n = 11 for Y‐27632 and diamide) and older (68 ± 7 years; n = 11 and 6 for Y‐27632 and diamide, respectively) adults using the luciferin‐luciferase technique following RBC incubation with either saline (control), Y‐27632, or diamide. The relative change in ATP release from normoxia to hypoxia in saline control conditions was impaired in RBCs from older (41.5 ± 12.1% and 63.5 ± 18.5%) vs. young (110.4 ±12.7% and 146.0 ± 29.3%) adults (P < 0.05; control trials for Y‐27632 and diamide, respectively). Y‐27632 improved RBC ATP release in older adults (98.8 ± 19.8%) such that it was not different from the young control (P > 0.05), whereas diamide decreased RBC ATP release in young adults (57.4 ± 8.4%) such that it was not different from the older control (P > 0.05). Preliminary data from our laboratory indicate that these drugs affected RBC membrane deformability as expected based on other reports of the effects of Y‐27632 and diamide on RBC membrane deformability. We conclude that decreased membrane deformability contributes to the impaired ability of RBCs from older adults to release ATP in response to Hb deoxygenation, and that this may have implications for impaired vascular control with advancing age. Support or Funding Information HL095573, HL119337, F31HL126377

ABSTRACT During infectious disease emergencies, it may be necessary to deploy new therapies without conclusive evidence for their effectiveness. During the SARS-CoV-2 pandemic, several countries used registries to track the use of COVID-19 convalescent plasma (CCP). Those registries provided evidence that CCP was effective when used early and with high titer.

Abstract Exercise intolerance and exertional dyspnoea are the cardinal symptoms of heart failure with reduced ejection fraction (HFrEF). In HFrEF, abnormal autonomic and cardiopulmonary responses arising from locomotor muscle group III/IV afferent feedback is one of the primary mechanisms contributing to exercise intolerance. HFrEF patients also have pulmonary system and respiratory muscle abnormalities that impair exercise tolerance. Thus, the primary impetus for this review was to describe the mechanistic consequences of locomotor muscle group III/IV afferent feedback and respiratory muscle work in HFrEF. To address this, we first discuss the abnormal autonomic and cardiopulmonary responses mediated by locomotor muscle afferent feedback in HFrEF. Next, we outline how respiratory muscle work impairs exercise tolerance in HFrEF through its effects on locomotor muscle O 2 delivery. We then discuss the direct and indirect evidence supporting an interaction between locomotor muscle group III/IV afferent feedback and respiratory muscle work during exercise in HFrEF. Last, we outline future research directions related to locomotor and respiratory muscle abnormalities to progress the field forward in understanding the pathophysiology of exercise intolerance in HFrEF.