The impact of COVID-19 has been largely described after symptom development. Although the SARS-CoV-2 virus elevates heart rate (HR) prior to symptom onset, whether this virus evokes other presymptomatic alterations is unknown. This Case Study details the presymptomatic impact of COVID-19 on vascular and skeletal muscle function in a young woman (24yrs, 173.5cm, 89kg, BMI: 29.6kg·m-2). Vascular and skeletal muscle function were assessed as part of a separate study with the first and second visits separated by 2 weeks. On the evening following the second visit, the participant developed a fever and a rapid antigen test confirmed a positive COVID-19 diagnosis. Compared to the first visit, the participant presented with a markedly elevated HR (~ 30 bpm) and lower mean blood pressure (~8 mmHg) at the second visit. Vascular function measured by brachial artery flow-mediated dilation, reactive hyperemia, and passive leg movement were all noticeably attenuated (25-65%) as was leg blood flow during knee extension exercise. Muscle strength was diminished as was ADP stimulated respiration (30%), assessed in vitro, while there was a 25% increase in the apparent Km. Lastly, an elevation in IL-10 was observed prior to symptom onset. Notably, 2.5 months after diagnosis symptoms of fatigue and cough were still present. Together, these findings provide unique insight into the physiological responses immediately prior to COVID-19 symptom onset; they suggest that SARS-CoV-2 negatively impacts vascular and skeletal muscle function prior to the onset of common symptoms and may set the stage for the widespread sequelae observed following COVID-19 diagnosis.

Background Hemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DL CO ) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise. Methods and Results Rebreathe DL CO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath‐by‐breath pulmonary gas exchange were recorded at rest, 20 W, and symptom‐limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m 2 ) achieved a lower symptom‐limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m 2 ). DL CO was lower in patients with HFpEF compared with controls at rest (DL CO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P <0.01) and symptom‐limited maximal exercise (DL CO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P <0.01) because of a lower alveolar‐capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P <0.01; symptom‐limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P <0.01). DL CO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient. Conclusions Lung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar‐capillary membrane. DL CO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

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AimsThe effect of extravascular lung water (EVLW) and relationship to functional status as a result of acute decompensated heart failure (ADHF) are not well understood. We sought to quantify changes in clinical variables, EVLW, airway anatomy, spirometry, and diffusing capacity for carbon monoxide before and after treatment for ADHF.Methods and resultsFifteen patients were recruited within 24 h of hospital admission. Spirometry, diffusing capacity for carbon monoxide, and surrogates of EVLW by computed tomography were measured and were then repeated within 24 h of discharge. From the computed tomography (CT) scan, surrogates of EVLW were calculated from the distribution of CT attenuation of the lung tissue. Airways were segmented using the vida apollo software. Patients were hospitalized for 4.6 ± 2.1 days, had 10 ± 4.8 L of fluid removed (7.0 ± 4.2 L between study visits), and lost 7.1 ± 4.9 kg. Patients had significant clearance of fluid from the lungs (per cent change: mean, 4.2 ± 6.1%; skew, 17.5 ± 27.0%; kurtosis, 37.6 ± 56.7%; full‐width half‐maximum, 10.2 ± 13.5%). Static lung volumes and maximal flows improved significantly (per cent change: forced vital capacity, 14.5 ± 13.6%; forced expiratory volume in 1 s, 15.9 ± 14.0%; forced expiratory flow at 25–75% of forced vital capacity, 27.2 ± 42.9%). The ratio of membrane conductance to capillary blood volume improved significantly (per cent change: alveolar–capillary membrane conductance/capillary blood volume, 23.4 ± 22.8%). Weight loss during hospitalization was significantly correlated with improved spirometry and diffusing capacity.ConclusionsExtravascular lung water contributes to the pulmonary congestive syndrome in ADHF patients, and its clearance is an important component of the improvement in pulmonary function as a result of inpatient treatment.

Purpose: Despite a growing body of literature on the physiological responses to ultramarathon, there is a paucity of data in females. This study assessed the female physiological response to ultramarathon and compared the frequency of perturbations to a group of race-and time-matched males. Methods: Data were collected from 53 contestants of an ultramarathon trail race at the Ultra-Trail du Mont-Blanc (UTMB®) in 2018/19. Before and within 2 h of the finish, participants underwent physiological assessments, including blood sampling for biomarkers (creatine kinase-MB isoenzyme [CK-MB], cardiac troponin I [cTnI], brain natriuretic peptide [BNP], and creatinine [Cr]), pulmonary function testing (spirometry, exhaled NO, diffusing capacities, and mouth pressures), and transthoracic ultrasound (lung comet tails, cardiac function). Data from eight female finishers (age = 36.6 ± 6.9 yr; finish time = 30:57 ± 11:36 h:min) were compared with a group of eight time-matched males (age = 40.3 ± 8.3 yr; finish time = 30:46 ± 10:32 h:min). Results: Females exhibited significant pre-to postrace increases in BNP (25.8 ± 14.6 vs 140.9 ± 102.7 pg•mL −1 ; P = 0.007) and CK-MB (3.3 ± 2.4 vs 74.6 ± 49.6 IU•L −1 ; P = 0.005), whereas males exhibited significant pre-to postrace increases in BNP (26.6 ± 17.5 vs 96.4 ± 51.9 pg•mL −1 ; P = 0.002), CK-MB (7.2 ± 3.9 vs 108.8 ± 37.4 IU•L −1 ; P = 0.002), and Cr (1.06 ± 0.19 vs 1.23 ± 0.24 mg•dL −1 ; P = 0.028). Lung function declined in both groups, but males exhibited additional reductions in lung diffusing capacities (DL CO = 34.4 ± 5.7 vs 29.2 ± 6.9 mL⋅min −1 ⋅mm Hg −1 , P = 0.004; DL NO = 179.1 ± 26.2 vs 152.8 ± 33.4 mL⋅min −1 ⋅mm Hg −1 , P = 0.002) and pulmonary capillary blood volumes (77.4 ± 16.7 vs 57.3 ± 16.1 mL; P = 0.002). Males, but not females, exhibited evidence of mild postrace pulmonary edema. Pooled effect sizes for within-group pre-to postrace changes, for all variables, were generally larger in males versus females (d = 0.86 vs 0.63). Conclusions: Ultramarathon negatively affects a range of physiological functions but generally evokes more frequent perturbations, with larger effect sizes, in males compared to females with similar race performances.

Background- Heart failure with preserved ejection fraction (HFpEF) patients experience symptoms of exertional dyspnea which may be related to lung fluid accumulation during exercise. A CT-based method was used to measure exercise-induced changes in extravascular lung fluid content and thoracic blood volumes and determine the effect of lung fluid on lung diffusing capacity for carbon monoxide (DLCO) in stable HFpEF subjects and healthy controls. Methods- Nine subjects with HFpEF (Age 68±8y, BMI 32.1±2.6kg/m2) and eight healthy controls (62±9y, 23.8±2.4kg/m2) performed triplicate re-breathe DLCO/DL­NO tests in a supine position at rest and duplicate measurements during two 5 min submaximal exercise stages (15 and 35W) and recovery. Subjects subsequently performed a 5 min exercise bout (35W) inside a CT scanner, and extravascular lung fluid content and thoracic blood volumes were quantified at rest and immediately following exercise from thoracic and contrast perfusion scans, respectively. Results-Subjects with HFpEF had a higher lung fluid content at rest compared to controls (Mean±SD, HFpEF: 14.4±1.7%, Control: 12.8±1.7%, p=0.043) and a higher lung fluid content following exercise (15.2±2.0% vs. 12.6±1.5%, p=0.009). Higher lung fluid content was associated with a lower DLCO and alveolar-capillary membrane conductance (Dm) in subjects with HFpEF (DLCO: R=-0.57, p=0.022, Dm: R=-0.61, p=0.012), but not in controls. Pulmonary blood volume was not altered by exercise and was similar between groups. Conclusions-Submaximal exercise elicited a greater accumulation of lung fluid in HFpEF compared to controls, and lung fluid content was negatively correlated with lung diffusing capacity and alveolar-capillary membrane conductance in HFpEF.

Aim The importance of endothelial cell (EC) autophagy to vascular homeostasis in the context of health and disease is evolving. Earlier we reported that intact EC autophagy is requisite to maintain shear-stress-induced nitric oxide (NO) generation via glycolysis-dependent purinergic signaling to eNOS. Here we illustrate the translational and functional significance of these findings. Methods and Results First, we assessed translational relevance using older male humans and mice that exhibit blunted EC autophagy and impaired arterial function vs. adult controls. Active hyperemia evoked by RHE elevated radial artery shear rate similarly from baseline in adult and older subjects for 60-min. Compared to baseline, indexes of autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs obtained from adult but not older volunteers. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older animals that completed 60-min treadmill-running. Further, 20 dyne • cm2 laminar shear stress x 45-min increased autophagic flux, glycolysis, ATP production, and p-eNOSS1177 in primary arterial ECs obtained from adult but not older mice. Concerning functional relevance, we next questioned whether the inability to initiate EC autophagy, glycolysis, and p-eNOSS1177in vitro precipitates arterial dysfunction ex vivo. Compromised intraluminal flow-mediated vasodilation displayed by arteries from older vs. adult mice was recapitulated in vessels from adult mice by : (i) NO synthase inhibition; (ii) acute autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) purinergic 2Y1-receptor (P2Y1-R) blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from : (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy. Conclusions Arterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.

Cardiovasomobility is a novel concept that encompasses the integration of cardiovascular and skeletal muscle function in health and disease with critical modification by physical activity, or lack thereof. Compelling evidence indicates that physical activity improves health while a sedentary, or inactive, lifestyle accelerates cardiovascular and skeletal muscle dysfunction and hastens disease progression. Identifying causative factors for vascular and skeletal muscle dysfunction, especially in humans, has proven difficult due to the limitations associated with cross-sectional investigations. Therefore, experimental models of physical inactivity and disuse, which mimic hospitalization, injury, and illness, provide important insight into the mechanisms and consequences of vascular and skeletal muscle dysfunction. This review provides an overview of the experimental models of disuse and inactivity and focuses on the integrated responses of the vasculature and skeletal muscle in response to disuse/inactivity. The time course and magnitude of dysfunction evoked by various models of disuse/inactivity are discussed in detail, and evidence in support of the critical roles of mitochondrial function and oxidative stress are presented. Lastly, strategies aimed at preserving vascular and skeletal muscle dysfunction during disuse/inactivity are reviewed. Within the context of cardiovasomobility, experimental manipulation of physical activity provides valuable insight into the mechanisms responsible for vascular and skeletal muscle dysfunction that limit mobility, degrade quality of life, and hasten the onset of disease.