Johnson, Bruce D.

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol . 22:249–262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO 2 ) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (F I O 2 : 0.125) and normoxia (F I O 2 : 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort ( n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO 2 was systematically higher after drug (peak exercise SaO 2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO 2 diff) and consumption (VO 2 ) were similar (peak exercise Ca-vO 2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO 2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO 2 was systematically higher after drug, whereas peak VO 2 was reduced (peak exercise SaO 2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO 2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO 2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

BACKGROUND Increased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF). PURPOSE The purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF. METHODS 8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO 2 ). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured. RESULTS HF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO 2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO 2 (p>0.05). CONCLUSION Inhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.

Background Locomotor muscle group III/IV afferent feedback contributes to sympathoexcitation. Sub‐systolic lower limb occlusion may stimulate this reflex. Purpose To examine the cardiovascular response to lower limb venous occlusion in healthy humans during rest and exercise. Methods Nineteen adults (9 men, 25±5 yr; mean±SD) participated in two visits. V1: 3 min seated rest followed by randomized bilateral thigh tourniquet inflation to 20, 40, 60, 80, 100 mmHg for 2 min with 2 min deflation between occlusions. V2: Recumbent cycle ergometer exercise at 30% peak work with occlusion described in V1. We measured mean, systolic and diastolic pressure, cardiac output, heart rate, and stroke volume (MAP, SBP, DBP, CO, HR, and SV, respectively). Results At rest, MAP (85±18 mmHg) increased at 100 mmHg (Δ4±5, p<0.05) mediated by increased DBP (71±15 mmHg) at 100 mmHg (Δ5±4, p<0.05) with no change in SBP. During exercise, MAP (89±11 mmHg) increased at 60 (Δ7±7), 80 (Δ14±8), and 100 (Δ16±8) mmHg occlusions via increased SBP (133±22 mmHg) at 60 (Δ12±14), 80 (Δ20±13), and 100 (Δ26±13) mmHg and DBP (68±9 mmHg) at 60 (Δ5±5), 80 (Δ10±7), and 100 (Δ12±7) (p<0.05, all). Although, CO and SV did not change, HR (108±11 bpm) increased at 40 (Δ5±4), 60 (Δ8±5), 80 (Δ13±7), and 100 mmHg (Δ15±7) (p<0.05, all). Conclusion Stimulation of locomotor muscle group III/IV afferents via sub‐systolic occlusion contributes to cardiovascular control.

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 Heart failure (HF) causes abnormal ventilatory responses to exercise which are inked to poor prognosis. We examined the impact of blocking fine afferents from locomotor muscles on exercise ventilatory efficiency in HF. Methods 9 HF patients (60±6yrs, LVEF 27±6%) and 9 healthy controls (63±7yrs) underwent two 5 min cycling sessions at 65% peak workload with and without intrathecal fentanyl. VO 2 , VCO 2 , V E , breathing frequency (fb), tidal volume (V T ), and chemoreceptor sensitivity (CO 2 rebreathe) were measured. Results Fentanyl did not influence exercise VO 2 in either group (HF=1.5±0.3 vs 1.5±0.3 L/min, control=1.7±0.4 vs 1.7±0.5 L/min). V E was lower with fentanyl in HF but not control (−12.3±7.1 vs 0.8±6.2%, p<0.001) due to lower fb (−10.5±4.6 vs 0.5±7.1%, p<0.01) with no change in V T (−1.2±9.4 vs 0.4±5.7%, p=0.67). V E /VCO 2 improved during exercise with fentanyl in HF but not in controls (−14.8±7.1 vs ‐ 0.5±7.0, p<0.01). Fentanyl did not influence chemoreceptor sensitivity in either group. Conclusion Blocking group III and IV afferent feedback from the locomotor muscles during exercise improves ventilatory efficiency in HF. NIH/NCRR grant KL2‐RR024151.

Background Heart failure (HF) is associated with impaired exercise pulmonary gas exchange (PGX) that is likely related to the development and severity of pulmonary hypertension (PH). Purpose To determine whether PGX measures differentiate HF patients with reactive PH from patients with passive PH or no PH. Methods/Results Pulmonary arterial pressure (P AP ), pulmonary wedge pressure (P WP ), transpulmonary pressure gradient (TPG) and PGX indices [end‐tidal CO 2 (P ET CO 2 ), ventilatory efficiency (V E /VCO 2 ), O 2 pulse, estimated pulmonary arterial capacitance (GX CAP )] were assessed simultaneously at rest and during cycle exercise in 38 HF patients undergoing right heart catheterization. Post hemodynamic evaluation, patients were classified as having no PH ( n = 12), passive PH ( n = 10) or reactive PH ( n = 16). TPG increased during exercise in all groups but was greater at end exercise in the reactive PH vs. the passive PH and no PH patients (21±9 vs. 14±7 vs. 12±7 mmHg). At an equivalent VO 2 , P ET CO 2 , O 2 pulse and GX CAP were higher and V E /VCO 2 ratio lower in the no PH and, to a lesser extent, in the passive PH vs. the reactive PH subjects (Figure 1). Conclusion Noninvasive measures of PGX during exercise appear to differentiate HF patients with reactive PH from patients with passive PH or no PH and may be a useful adjunct to invasive catheterization in assessing PH type and severity. HL71478, AHA12POST12070084, Gilead Science

BACKGROUND Psycho‐socio stressors may over time result in dominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PNS). Reduced PNS control over cardiovascular processes has been associated with decreased health. Heart rate variability (HRV) has been proposed as a technique to quantify SNS and PNS interactions and thus might offer a noninvasive predictive index. OBJECTIVE To investigate the impact of real‐life stressors on HRV fluctuations in independent living elders (EL). METHODS For three months every two weeks EL (N=22; Age=75±9; M/F ratio=17/5) performed autonomic tests consisting of quiet breathing, paced breathing and hand grip. All did a questionnaire assessing depression, positive/negative live events, and isolation. RESULTS Negative events (r=0.36, p=.01) and isolation (r=0.35, p=0.02) are correlated with HR. Personal changes in HRV, SDNN (r=−0.43, p<0.005) and Poincare Width (r= −0.42, p<0.005), are correlated to negative life events. CONCULSION Negative life events reduce HRV which suggests either SNS activation and/or PNS withdrawal. Research was made possible by Healthy for Life, TNO, and the Center for Innovation, Mayo Clinic.

Introduction Optivol (Medtronic Inc.) thoracic impedance (ZT) provides preemptive disease status information in heart failure (HF). It remains unclear how pulmonary‐capillary blood volume (Vc), lung volume (Lvol), and interstitial fluid influence ZT. Hypothesis Positional change and exercise result in increased Vc and/or lung interstitial fluid and ZT tracks fluctuation in these variables. Methods 12 HF patients (age 63±8yr, LVEF 41±14%) were recruited. Measures were taken at rest, exercise, recovery. This included: spirometry, ZT, diffusing capacity of the lungs for CO and NO (DLCO, DLNO), alveolar‐capillary conductance (Dm, interstitial fluid index), and Vc. Inspiratory capacity was obtained to provide consistent lung volumes for assessing ZT. Results Positional change (upright‐supine) resulted in an increased ZT (5±4%, p<0.01), while the change in Lvol (RV‐TLC) resulted in a 7±2 ohm swing in ZT (0.2±0.1ohm change/100ml change in Lvol). After 30min supine, Vc increased 28±39% (p<0.05) while Dm/Vc and Lvol decreased (29±11% and 17±3%, p<0.05). During exercise compared to baseline, Vc increased 56±44% (p<0.01), DmCO/Vc decreased 25±7% (p<0.05), and ZT did not change. During recovery measures normalized except DmCO/Vc. Conclusion Positional changes and fluctuations in Lvol influence ZT yet measures of lung fluid minimally impact this measure despite significant fluctuations.