Snyder, Eric M.

Background : Research suggests the beta‐1 adrenergic receptor (ADRB1) has been shown to play a functional role in cardiomyocyte function and accounts for up to 80% of the cardiac tissue adrenergic receptors with ADRB1 stimulation increasing cardiac rate, contractility, and work. Multiple polymorphisms of the ADRB1 have been identified such as the Gly49 polymorphism that includes at least one glycine (Gly) for serine (Ser) at amino acid 49 resulting in either homozygous for Gly (Gly49Gly) or heterozygous for Gly (Gly49Ser) polymorphisms. The Gly49 polymorphism has been shown to have decreased receptor density, decreased cAMP accumulation, and a dampening influence on the cardiostimulant effect during norepinephrine infusion. Heart failure patients with this polymorphism (Gly49) have also been shown to have improved cardiac function and decreased mortality risk, but if there is an effect in healthy subjects is less clear. This suggests the Gly49 polymorphism may have cardioprotective effects similar to that of a beta‐blocker. Purpose The purpose of this study was to determine the effects of the Gly/Ser polymorphism at position 49 of the ADRB1on the cardiovascular response to exercise in healthy subjects. Methods We performed genotyping of the ADRB1 (amino acid 49) and high‐intensity, steady‐state exercise on 71 healthy subjects (Ser49Ser = 52, Gly49Ser = 19). Results There were no differences between genotype groups in age, height, weight, BMI, or watts achieved (age = 28.9 ± 5.6yrs., 30.6 ± 6.4yrs., height = 173.6 ± 9.9cm, 174 ± 7.5cm, weight = 74.4 ± 13.3kg, 71.9 ± 13.5kg, BMI = 24.6 ± 3.5, 23.6 ± 3.3, and watts = 223.8 ± 76.8, 205 ± 49.4, for Ser49Ser and Gly49Ser respectively). Additionally, there were no differences for genotype groups for cardiac output (CO), systolic blood pressure (BP sys ), or diastolic blood pressure (BP dias ) at rest, peak exercise, or in change from rest to peak exercise. The genotype groups differed significantly in heart rate (HR max ) at peak exercise and cardiac index at rest (CI) (HR max = 184.2 ± 9.5bpm, 190.7 ± 10.6bpm, CI = 0.063 ± 0.014, 0.071 ± 0.013, for Ser49Ser and Gly49Ser respectively). There was a trend towards significance (p = 0.058) for the change in stroke volume from rest to peak exercise (ΔSV) (0.016 ± 0.018L, 0.0076 ± 0.012L, for Ser49Ser and Gly49Ser respectively). Conclusion : These data suggest genetic variations of the ADRB1 may influence cardiovascular responses to exercise in healthy subjects. Support or Funding Information NIH grants: HL108962‐06 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The causes of reduced pulmonary function (PF) in heart failure (HF) patients remain unclear, but may be due to increased pulmonary congestion. Rapid fluid loading (RFL) in healthy adults has been used to simulate intra‐thoracic fluid overload common in HF. This study examined PF using plethysmography, and airway lumen cross sectional area (A lumen ), airway wall thickness (t aw ), and vascular volume using non‐contrast CT imaging before and after RFL in 22 healthy adults. Average infusion volume was 2190 ± 412 ml over 20 ± 3 min. Vascular volume, heart rate, and cardiac output increased (p<0.001). O 2 saturation and mean arterial pressure were unchanged. Forced vital capacity (FVC) and expiratory flow measures decreased post RFL (ΔFVC=−13±9%, ΔFEV1=−15±10%, ΔFEF25‐75=−17±19%, p<0.001). A lumen was unchanged from the trachea through airway generation 3; t aw decreased in the trachea (p<0.05) but remained unchanged in airway generations 1–3. Both measures increased at airway generation 4 (p<0.01). Changes in t aw and A lumen were unrelated and were also independent of any changes in vascular volume or PF. This data suggests that RFL in healthy adults results in decreases in PF, however these decreases are not due to changes in A lumen , t aw , or pulmonary blood volume of the larger airways and vessels that can be easily imaged without contrast. Further studies will be needed to assess bronchial changes in the mid to smaller airways.

Background Increased pulmonary capillary pressure and a possible desensitization of lung β 2 adrenergic receptors (β 2 AR) involved in fluid removal mechanisms may increase extravascular lung water (E LW ) in stable heart failure (HF) patients. Whether these patients exhibit increased E LW remains controversial. Purpose To determine if HF patients have elevated E LW versus controls (CTL) and if acute β 2 AR agonist inhalation stimulates fluid removal. Methods/Results 14 stable HF patients and 19 healthy age/gender matched CTL were studied. Lung tissue volume (V tis ) (includes tissue, blood and water) and pulmonary capillary blood volume (Vc) were assessed pre and post nebulized albuterol via CT and rebreathe, respectively. E LW was derived as V tis – Vc. Pre albuterol, E LW was greater in HF vs. CTL (861±241 vs. 739±143 ml, P <0.01), with no difference in V tis (938±246 vs. 830±151 ml, P =0.08). Albuterol decreased V tis (–4±2%, P =0.02) but did not change E LW (739±143 vs. 724±132 ml) ( P >0.05) in CTL. In HF, albuterol decreased both V tis (–5±3%) and E LW (– 4±2%) ( P <0.05). There was a negative relationship between baseline values and the pre to post albuterol change for V tis ( r 2 =0.38) and E LW ( r 2 =0.42) ( P <0.01) in HF. Conclusion Lung fluid is elevated in stable HF patients relative to healthy subjects. Stimulation of β 2 ARs appears to enhance fluid removal in HF, especially in patients with elevated lung water at rest.

Our lab has demonstrated a lower cardiac output (Q) in patients with heart failure (HF) vs. controls (CTL) using acetylene rebreathing (ACET). This technique may be dependent on lung health, which is altered in HF. Therefore, we examined the relationship between Q from echocardiography (echo) and Q from ACET at rest and during exercise. Additionally, we examined the relationship between stroke volume (SV) estimated from O 2 pulse compared to SV by ACET (SV A ). 26 controls (CTL) and 18 HF patients with preserved ejection fraction (EF) completed an exercise test on a cycle ergometer. Lung conductance was measured by lung diffusion for carbon monoxide (DL CO ). Measures of Q (Q A , Acetylene rebreathe; Q E , transthoracic echo), heart rate (HR, 12‐lead ECG), and oxygen consumption (VO 2 , metabolic cart) were taken at rest and peak exercise. Stroke volume (SV) and O 2 pulse were calculated as Q/HR and VO 2 /HR, respectively. HF patients had lower DL CO compared to CTL (Rest: DL CO =11±0.5 vs 14±0.6 ml/min/mmHg, p<0.05). At rest and exercise, Q E was moderately correlated with Q A in CTL (Rest: r=0.47; Pk Ex: r=0.51, p<0.05) and HF (rest: r=0.47; Pk Ex: r=0.77, p<0.05). O 2 pulse was significantly related to SV A at rest and exercise in CTL (Rest: r=0.76; Pk Ex: r=0.81, p<0.05) and HF (Rest: r=0.81; Pk Ex: r=0.82, p<0.05). Cardiac function assessed via ACET is related to cardiac function by echo and O 2 pulse in patients with HF with preserved EF.

Purpose Oxygen pulse (O 2 pulse) is often used clinically as a surrogate for stroke volume during cardiopulmonary exercise testing; however, little data exists on the validity of this measure in patient populations (e.g. heart failure with preserved ejection fraction – HFpEF). Therefore, the purpose of this study was to examine the relationship between O 2 pulse and stroke volume (SV) measured using an accepted technique, echocardiography, at rest and during exercise. Methods Eighteen HFpEF (EF=62±1%) patients and 26 healthy controls (CTL) completed an exercise test on a cycle ergometer. Average measures of oxygen consumption (VO 2 , metabolic cart), heart rate (HR, 12‐lead ECG), and SV (transthoracic echocardiography) were taken at rest and peak exercise. O 2 pulse was calculated as VO 2 divided by HR. Results O 2 pulse was significantly correlated with SV at rest and at peak exercise in CTL (r=0.60 and r=0.55, p<0.05 for both respectfully). O 2 pulse was similarly significantly correlated with SV at rest in HFpEF (r=0.58, p<0.05) whereas this relationship demonstrated a trend at peak exercise (r=0.44, p=0.06). Conclusion Our results demonstrate a moderate relationship between O 2 pulse and SV measured using echocardiography in healthy control participants at rest and during exercise. There is a similar relationship at rest in patients with HFpEF; however, this relationship is less strong during exercise.

Asthma, chronic obstructive pulmonary disease, and other respiratory disorders often occur concurrently with heart failure (HF). HF patients with respiratory disease can improve lung function and, therefore, quality of life with β‐agonists. Beta‐agonist use remains controversial as it has been linked with increased mortality risk; however, recent studies that account for co‐morbidities find no association between β‐agonist use and mortality. Previous studies exploring the cardiovascular effect of β‐agonist use in HF are primarily retrospective and focus on heart rate (HR). We have previously demonstrated altered cardiovascular function in response to albuterol in healthy subjects. In the present study we sought to comprehensively assess the cardiovascular effects of albuterol sulfate using cardiac output (Q), stroke volume (SV), HR, systolic, diastolic, and mean arterial blood pressure (SBP, DBP, MAP, respectively) and systemic vascular resistance (SVR). We hypothesized that cardiovascular parameters would be altered 30‐minutes following albuterol administration, and that HF patients using β‐blockers would have an attenuated response. Twenty‐two healthy and twenty‐two HF subjects were recruited (age=56±13 vs. 62±12yrs; height=175±10 vs. 176±9cm; weight=78±15 vs. 93±20; BMI=26±4 vs. 30±6; and BSA=2.08±0 vs. 1.93±0m 2 , for healthy and HF, respectively, p<0.05 for weight, BMI, and BSA). We found that HR and Q increased in healthy but not HF subjects at 30min following albuterol. Patients who were not on β‐blockers (n=4, 18%) had an increase in SV and a decrease in SVR with albuterol, while there was no change in patients who were on β‐blockers (n=14, 64%). These data suggest that HF patients have an attenuated cardiovascular response to inhaled albuterol, particularly with concurrent β‐blocker usage.

Background Fluid flux in the lungs is influenced by factors altering accumulation or removal (e.g., stimulation of epithelium sodium channels, ENaC). Purpose To determine if ENaC are necessary in the normal fluid regulation with simulated altitude exposure. Methods/Results On separate occasions, 19 healthy subjects (27 ± 5 y) received either nebulized amiloride (ENaC antagonist) or placebo (nebulized saline) during 17 h normobaric hypoxia (FIO2 = 12.5%) in a randomized, double‐blind fashion. Lung diffusing capacity for carbon monoxide (DLCO), alveolar‐capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) were measured via a rebreathe method before and after hypoxic exposure. DLCO was not different at baseline for the amiloride vs. placebo treatments (19 ± 5 vs. 21 ± 8 mL/min/mmHg). Hypoxic exposure increased Vc but did not change Dm in both treatments (Placebo: Vc = 43 ± 22 vs. 59±23 mL p=0.011, Dm = 35 ± 10 vs. 37 ± 12 mL/min/mmHg p=0.312; Amiloride: Vc = 38 ± 17 vs. 57 ± 22 mL p<0.01, Dm = 31 ± 8 vs. 34 ± 10 mL/min/mmHg p= 0.206). Conclusion Normobaric hypoxia did not differentially affect alveolar‐capillary conductance in amiloride and placebo conditions, suggesting that ENaC do not have a role in normal lung fluid regulation during acute hypoxic exposure. HL71478

Fluid clearance from the alveolar space is critically dependent on epithelial sodium channels (ENaC). A common polymorphism in the gene encoding the ENaC alpha subunit results in an alanine to threonine substitution (A663T), with higher ENaC channel activity. This variant influences ion and fluid regulation in the lung during exercise and in response to albuterol. We investigated the influence of the threonine variant (T663; AT/TT group) on the lung fluid response to exercise in conditions of normobaric hypoxia, which challenges lung fluid balance. Lung fluid balance was assessed using Exhaled Na + (ENa + ) and the diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar‐capillary membrane conductance (Dm). 19 healthy subjects were grouped by ENaC genotype (n=8 vs. 11 for AA and AT/TT, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m 2 ) and completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo or inhaled amiloride (1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa + , DLCO, and Dm assessed at baseline, following 12 hours of hypoxic exposure, and following hypoxic exercise at 65% peak power on a cycle ergometer. We found significant effects of the interaction between gender and ENaC genotype on DLCO, Dm, and Dm corrected for pulmonary capillary blood volume (p<0.05). Specifically, females with the more active T663 variant had a greater diffusing capacity and less ENa + under placebo conditions, suggesting a greater removal of Na + and fluid from the airspace. These results suggest that genetic variation of ENaC may influence lung fluid balance during hypoxia and hypoxic exercise. Grant Funding Source : Supported by HL71478, HL108962‐03, and HL007249

Background Exposure to hypoxia causes pulmonary vasoconstriction (HPV) and may contribute to the pathogenesis of HAPE. The site of HPV, however, is controversial. While the majority of data suggests HPV occurs in the pulmonary arterioles (precapillary), there is evidence that HPV may also occur in postcapillary vessels. Expansion of pulmonary capillary blood volume (Vc) is primarily passive and thus closely linked to cardiac output (Q). Purpose To examine relationships between Q and Vc during exposure to hypoxia and fluid loading. Methods/Results Healthy adults (n=25, age=31±2 yr) reported to the lab for 2 exposures: 1) 17‐h 12.5% F I O 2 in a hypoxia tent, and 2) fluid loading using IV saline (30 ml/kg over ~15 min). Q, Vc and Dm (alveolar‐capillary conductance) were measured using a rebreathe method with small amounts of C 2 H 2 , CO and NO gas. Saline infusion caused an increase in Q (32±6%, P <0.01) and Vc (39±13%, P <0.05), and a decrease in Dm (−9±3%, P <0.05). Vc/Q was not different pre‐ vs post‐saline (17±2 vs 18±3, P =0.40). Hypoxic exposure caused an increase in pulmonary arterial pressure (67±11%, P <0.01), Vc (57±20%, P =0.04) and Dm (35±6%, P <0.01) despite no change in Q (0.2±2.8%, P =0.98). Vc/Q was greater post‐ vs. pre‐hypoxia (24±4 vs. 17±2, P =0.06). Conclusion The rise in Vc with a constant Q during hypoxic exposure suggests a post capillary site for HPV causing the expansion of the pulmonary capillary bed. HL71478.