Influence of ß2 adrenergic receptor genotype on risk of nocturnal ventilation in patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3-25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.

Beta-2 Adrenergic Receptor Genotype Influences Power Output in Healthy Subjects.

Kelley, EF, Johnson, BD, and Snyder, EM. Beta-2 adrenergic receptor genotype influences power output in healthy subjects. J Strength Cond Res 31(8): 2053-2059, 2017-The purpose of this study was to determine the effects of ADRB2 genotypes on muscle function (absolute power and relative power) in healthy subjects. We performed genotyping of the ADRB2 (amino acid 16) and high-intensity, steady-state exercise on 77 healthy subjects (AA = 18, AG = 25, GG = 34). There were no differences between genotype groups in age, height, weight, or body mass index (BMI) (age = 28.9 ± 5.7 years, 27.9 ± 5.7 years, 29.2 ± 5.9 years, height = 170.7 ± 8.6 cm, 174.9 ± 8.7 cm, 173.4 ± 9.6 cm, weight = 68.5 ± 13.0 kg, 75.0 ± 12.9 kg, 74.4 ± 12.9 kg, and BMI = 23.4 ± 3.9, 24.4 ± 2.9, 24.7 ± 3.4, for AA, AG, and GG, respectively). The genotype groups differed significantly in watts, and watts/V[Combining Dot Above]O2 with heavy exercise (watts = 186.3 ± 54.6, 237.8 ± 54.4, 219.4 ± 79.5, watts/V[Combining Dot Above]O2 = 0.08 ± 0.006, 0.09 ± 0.005, 0.08 ± 0.006). There was a trend toward significance (p = 0.058) for W·kg (2.7 ± 0.4, 3.2 ± 0.5, 2.9 ± 0.8, for AA, AG, and GG, respectively). These data suggest that genetic variation of the ADRB2 may influence relative strength in healthy subjects and may become an important genetic determinant of muscular strength and functional capacity in patients with diseases that result in a loss of muscle strength.

Expiratory Threshold Loading and Attentional Performance.

INTRODUCTION: While there are numerous factors that may affect pilot attentional performance, we hypothesize that an increased expiratory work of breathing experienced by fighter pilots may impose a "distraction stimulus" by creating an increased expiratory effort sensation. Therefore, the purpose of this study was to determine the extent to which increasing expiratory pressure time product or expiratory effort sensation impacts attentional performance.METHODS: Data was collected on 10 healthy participants (age: 29 ± 6 yr). Participants completed six repetitions of a modified Masked Conjunctive Continuous Performance Task protocol while breathing against four different expiratory threshold loads. Repeated measures analysis of variances and generalized additive mixed effects models were used to investigate the effects of expiratory threshold load conditions on expiratory pressure time product, expiratory effort sensation, and the influence of altered end tidal gases on Masked Conjunctive Continuous Performance Task scores.RESULTS: The overall median hit reaction times were significantly longer as the expiratory threshold loads increased. Specific shape-conjunctive and non-conjunctive median hit reaction times were longer with increased expiratory effort sensation. Additionally, increased expiratory effort sensation did not significantly change commission error rates, but did significantly increase omission error rates.DISCUSSION: The findings of our work suggest that both progressively greater expiratory threshold loads during spontaneous breathing and expiratory effort sensation may impair subjects' attentional performance due to longer reaction times and increased stimuli recognition error rates.Kelley EF, Cross TJ, Johnson BD. Expiratory threshold loading and attentional performance. Aerosp Med Hum Perform. 2024; 95(7):367-374.

Metabolic insights at the finish line: deciphering physiological changes in ultramarathon runners through breath VOC analysis.

Exhaustive exercise can induce unique physiological responses in the lungs and other parts of the human body. The volatile organic compounds (VOCs) in exhaled breath are ideal for studying the effects of exhaustive exercise on the lungs due to the proximity of the breath matrix to the respiratory tract. As breath VOCs can originate from the bloodstream, changes in abundance should also indicate broader physiological effects of exhaustive exercise on the body. Currently, there is limited published data on the effects of exhaustive exercise on breath VOCs. Breath has great potential for biomarker analysis as it can be collected non-invasively, and capture real-time metabolic changes to better understand the effects of exhaustive exercise. In this study, we collected breath samples from a small group of elite runners participating in the 2019 Ultra-Trail du Mont Blanc ultra-marathon. The final analysis included matched paired samples collected before and after the race from 24 subjects. All 48 samples were analyzed using the Breath Biopsy Platform with GC-Orbitrap™ via thermal desorption gas chromatography-mass spectrometry. The Wilcoxon signed-rank test was used to determine whether VOC abundances differed between pre- and post-race breath samples (adjustedP-value < .05). We identified a total of 793 VOCs in the breath samples of elite runners. Of these, 63 showed significant differences between pre- and post-race samples after correction for multiple testing (12 decreased, 51 increased). The specific VOCs identified suggest the involvement of fatty acid oxidation, inflammation, and possible altered gut microbiome activity in response to exhaustive exercise. This study demonstrates significant changes in VOC abundance resulting from exhaustive exercise. Further investigation of VOC changes along with other physiological measurements can help improve our understanding of the effect of exhaustive exercise on the body and subsequent differences in VOCs in exhaled breath.

A Systematic Review of Methods Used to Determine the Work of Breathing during Exercise.

INTRODUCTION: Measurement of the work of breathing (Wb) during exercise provides useful insights into the energetics and mechanics of the respiratory muscles across a wide range of minute ventilations. The methods and analytical procedures used to calculate the Wb during exercise have yet to be critically appraised in the literature. PURPOSE: The aim of this systematic review was to evaluate the quality of methods used to measure the Wb during exercise in the available literature. METHODS: We conducted an extensive search of three databases for studies that measured the Wb during exercise in adult humans. Data were extracted on participant characteristics, flow/volume and pressure devices, esophageal pressure (P oes ) catheters, and methods of Wb analysis. RESULTS: A total of 120 articles were included. Flow/volume sensors used were primarily pneumotachographs ( n = 85, 70.8%), whereas the most common pressure transducer was of the variable reluctance type ( n = 63, 52.5%). Esophageal pressure was frequently obtained via balloon-tipped catheters ( n = 114, 95.0%). Few studies mentioned calibration, frequency responses, and dynamic compensation of their measurement devices. The most popular method of measuring the Wb was pressure-volume integration ( n = 51, 42.5%), followed by the modified Campbell ( n = 28, 23.3%) and Dean & Visscher diagrams ( n = 26, 21.7%). Over one-third of studies did not report the methods used to process their pressure-volume data, and the majority (60.8%) of studies used the incorrect Wb units and/or failed to discuss the limitations of their Wb measurements. CONCLUSIONS: The findings of this systematic review highlight the need for the development of a standardized approach for measuring Wb, which is informative, practical, and accessible for future researchers.

Inspiratory threshold loading negatively impacts attentional performance.

Rationale: There are growing concerns over the occurrence of adverse physiologic events (PEs) occurring in pilots during operation of United States Air Force and Navy high-performance aircraft. We hypothesize that a heightened inspiratory work of breathing experienced by jet pilots by virtue of the on-board life support system may constitute a "distraction stimulus" consequent to an increased sensation of respiratory muscle effort. As such, the purpose of this study was to determine whether increasing inspiratory muscle effort adversely impacts on attentional performance. Methods: Twelve, healthy participants (age: 29 ± 6 years) were recruited for this study. Participants completed six repetitions of a modified Masked Conjunctive Continuous Performance Task (MCCPT) protocol while breathing against four different inspiratory threshold loads to assess median reaction times (RTs). A computer-controlled threshold loading device was used to set the inspiratory threshold loads. Repeated measures analysis of variances (ANOVAs) were performed to examine: (i) the efficacy of the threshold loading device to impose significantly higher loading at each loading condition; (ii) the effects of loading condition on respiratory muscle effort sensation; and (iii) the influence of hypercapnia on MCCPT scores during inspiratory threshold loading. Generalized additive mixed effects models (GAMMs) were used to examine the potential non-linear effects of respiratory muscular effort sensation, device loading, and hypercapnia, on MCCPT scores during inspiratory threshold loading. Results: Inspiratory threshold loading significantly augmented (P < 0.05) inspiratory effort sensation and the inspiratory pressure-time product (PTP). Our analyses also revealed that median hit RT was positively associated with inspiratory effort sensation during inspiratory loading trials. Conclusion: The findings of this work suggest that it was not increasing inspiratory muscle effort (i.e., PTP) per se, but rather participant's subjective perception of inspiratory "load" that impacts negatively on attentional performance; i.e., as the degree of inspiratory effort sensation increased, sotoo did median hit RT. As such, it is reasonable to suggest that minimizing inspiratory effort sensation (independent of the mechanical output of the inspiratory muscles) during high-performance flight operations may prove useful in reducing pilot RTs during complex behavioral tasks.

Influence of ß2 adrenergic receptor genotype on longitudinal measures of forced vital capacity in patients with Duchenne muscular dystrophy.

The progression of decline in forced vital capacity as percent predicated (FVC%p) is a strong indicator of worsening prognosis in patients with Duchenne muscular dystrophy (DMD). Evidence suggests that ß2 adrenergic (ADRB2) receptors may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function. The purpose of this study was to determine the influence of ADRB2 genotype on longitudinal measures of FVC%p as a function of age in DMD patients. Data from the CINRG Duchenne Natural History Study including 169 DMD patients (5-25 yrs) were analyzed. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of FVC%p across patient ages between genotype groups after controlling for patient demographics, corticosteroid-use, and ambulatory status. Both genotype groups displayed a progressive, maturational decline in FVC%p. Notwithstanding this decline, patients expressing the Gly16 polymorphism demonstrated systematically lower FVC%p values at any given age compared with patients expressing the Arg16 polymorphism (P < 0.01). Therefore, expressing the Gly16 polymorphism may prove detrimental to respiratory function in DMD patients. These data suggest maybe ADRB2 genotyping should be considered in the clinical management of DMD patients.

Influence of rapidly oscillating inspired O2 and N2 concentrations on pulmonary vascular function and lung fluid balance in healthy adults.

Introduction: Aircrew may experience rapidly oscillating inspired O2/N2 ratios owing to fluctuations in the on-board oxygen delivery systems (OBOG). Recent investigations suggest these oscillations may contribute to the constellation of physiologic events in aircrew of high-performance aircraft. Therefore, the purpose of this study was to determine whether these "operationally-relevant" environmental challenges may cause decrements in measures of pulmonary vascular physiology. Methods: Thirty healthy participants (Age: 29 ± 5 years) were recruited and assigned to one of the three exposures. Participants were instrumented for physiologic monitoring and underwent baseline cardiopulmonary physiology testing (ground level) consisting of a rebreathe method for quantifying pulmonary blood flow (Qc), pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (Dm). Ultrasound was used to quantify "comet tails" (measure of lung fluid balance). After baseline testing, the participants had two 45 min exposures to an altitude of 8,000 ft where they breathed from gas mixtures alternating between 80/20 and 30/70 O2/N2 ratios at the required frequency (30 s, 60 s, or 120 s), separated by repeat baseline measure. Immediately and 45 min after the second exposure, baseline measures were repeated. Results: We observed no changes in Qc, Dm or Vc during the 60 s exposures. In response to the 30 s oscillation exposure, there was a significantly reduced Qc and Vc at the post-testing period (p = 0.03). Additionally, exposure to the 120 s oscillations resulted in a significant decrease in Vc at the recovery testing period and an increase in the Dm/Vc ratio at both the post and recovery period (p < 0.01). Additionally, we observed no changes in the number of comet tails. Conclusion: These data suggest "operationally-relevant" changes in inspired gas concentrations may cause an acute, albeit mild pulmonary vascular derecruitment, reduced distention and/or mild pulmonary-capillary vasoconstriction, without significant changes in lung fluid balance or respiratory gas exchange. The operational relevance remains less clear, particularly in the setting of additional environmental stressors common during flight (e.g., g forces).

Influence of ß1 Adrenergic Receptor Genotype on Longitudinal Measures of Left Ventricular Ejection Fraction and Responsiveness to ß-Blocker Therapy in Patients With Duchenne Muscular Dystrophy.

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on ß1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures.

The Effect of Genetically Guided Mathematical Prediction and the Blood Pressure Response to Pharmacotherapy in Hypertension Patients.

PURPOSE: The purpose of this study was to determine the effectiveness of a simple algorithm to mathematically predict a patients' response to blood pressure (BP) therapy using functional genes in the 3 major organ systems involved in hypertension. METHODS: Eighty-six patients with controlled hypertension completed 1 study visit consisting of a buccal swab collection, measurement of office BP, and a medical chart review for BP history. Genes in the analysis included 14 functional alleles in 11 genes. These genotypes were mathematically summed per organ system to determine whether a patient would likely respond to target therapy. RESULTS: Patients recommended to and taking a diuretic had significantly higher rates of control (<120/<80) than patients recommended but not taking this drug class (0.2 ± 0.1 and 0.03 ± 0.03, respectively). Furthermore, there was a difference between patients genetically recommended and taking an angiotensin receptor blocker (ARB) vs patients recommended but not taking an ARB for the lowest diastolic blood pressure (DBP) and mean arterial pressure (MAP) recorded in the past 2 years (DBP = 66.2 ± 2.9 and 75.3 ± 1.7, MAP = 82.3 ± 2.8 and 89.3 ± 1.5, respectively). In addition, there was a nonsignificant trend for greater reductions in ΔSBP, ΔDBP, and ΔMAP in patients on recommended drug class for beta-blockers, diuretics, and angiotensin II receptor blockers vs patients not on these classes. CONCLUSION: The present study suggests that simple mathematical weighting of functional genotypes known to control BP may be ineffective in predicting control. This study demonstrates the need for a more complex, weighted, multigene algorithm to more accurately predict BP therapy response.

The syringe potentiometer: a low-cost device for pneumotachograph calibration.

The purpose of this report was to 1) detail the construction of a low-cost device that provides a "reference" flow waveform for pneumotachograph (PNT) calibration, i.e., the "syringe potentiometer" (SP), and to compare the 2) accuracy and 3) practical performance of "calibration curves" obtained with the SP device to other more established methods of PNT calibration, i.e., the weighted averaging (WA) and polynomial least-squares (PolyLS) methods. Volume and flow waveforms obtained via the SP device were validated against a motion capture system and were deemed accurate surrogates of actual syringe volume and flows. The SP device was used to construct a calibration curve of a PNT by dividing the flow waveform of the SP by the analog output of the PNT amplifier. A total of 187 inspiratory and 187 expiratory strokes were collected. When the entire data set of expiratory strokes was used, the SP, WA, and PolyLS methods together demonstrated acceptable volume and flow errors as per American Thoracic Society/European Respiratory Society recommendations (less than ±3.5% and less than ±5.0% errors, respectively). The "practical" performance of each method was assessed with a nested subsampling procedure, whereby volume and flow errors were evaluated as the number of strokes was increased (in blocks of 5 strokes). To this end, the SP method demonstrated practical performance superior to that of the WA and PolyLS approaches, whereby acceptable volume and flow errors were achieved after only 5 calibration strokes; the WA and PolyLS methods required 15 and 20 strokes, respectively, to achieve the same level of volume and flow accuracy.NEW & NOTEWORTHY This report describes the construction and validation of a low-cost device for the purposes of pneumotachograph (PNT) calibration: the "syringe potentiometer" (SP). Calibration of a PNT with the SP device yielded acceptable volume and flow errors (<3.5% and 5%, respectively) across a wide range of flows (<0.5 to 15 L/s). The SP device offered superior "practical performance" over other established PNT calibration methods, whereby acceptable volume and flow errors were achieved after only five calibration strokes.

Relationship between a Weighted Multi-Gene Algorithm and Blood Pressure Control in Hypertension.

Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1⁻4 as most to least likely to respond based on the algorithmic assessment of individual patient's genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.

Influence of Beta-1 Adrenergic Receptor Genotype on Cardiovascular Response to Exercise in Healthy Subjects.

BACKGROUND: 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. Heart failure patients with this polymorphism (Gly49) have been shown to have improved cardiac function and decreased mortality risk, but if there is an effect in healthy subjects is less clear. 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, body mass index (BMI), or watts achieved (age = 28.9 ± 5.6 years (yrs.), 30.6 ± 6.4yrs., height = 173.6 ± 9.9 cm, 174 ± 7.5 cm, weight = 74.4 ± 13.3 kg, 71.9 ± 13.5 kg, 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 (BPsys), or diastolic blood pressure (BPdias) at rest, maximal exercise, or in change from rest to maximal exercise. The genotype groups differed significantly in heart rate (HRmax) at maximal exercise and cardiac index at rest (CI) (HRmax = 184.2 ± 9.5 bpm, 190.7 ± 10.6 bpm, 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 ± 0.018 L, 0.0076 ± 0.012 L, for Ser49Ser and Gly49Ser respectively). CONCLUSIONS: These data suggest genetic variations of the ADRB1 may influence cardiovascular responses to exercise in healthy subjects.

Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study.

AIMS: Hypertension is the strongest modifiable risk factor for cardiovascular disease, affecting 80 million individuals in the US and responsible for ∼360,000 deaths, at total annual costs of $93.5 billion. Antihypertension therapies guided by single genotypes are clinically more effective and may avert more adverse events than the standard of care of layering anti-hypertensive drug therapies, thus potentially decreasing costs. This study aimed to determine the economic benefits of the implementation of multi-gene panel guided therapies for hypertension from the payer perspective within a 3-year time horizon. MATERIALS AND METHODS: A simulation analysis was conducted for a panel of 10 million insured patients categorized clinically as untreated, treated but uncontrolled, and treated and controlled over a 3-year treatment period. Inputs included research data; empirical data from a 11-gene panel with known functional, heart, blood vessel, and kidney genotypes; and therapy efficacy and safety estimates from literature. Cost estimates were categorized as related to genetic testing, evaluation and management, medication, or adverse events. RESULTS: Multi-gene panel guided therapy yielding savings of $6,256,607,500 for evaluation and management, $908,160,000 for medications, and $37,467,508,716 for adverse events, after accounting for incremental genetic testing costs of $2,355,540,000. This represents total 3-year savings of $42,276,736,216, or a 47% reduction, and 3-year savings of $4,228 and annual savings of $1,409 per covered patient. CONCLUSIONS: A precision medicine approach to genetically guided therapy for hypertension patients using a multi-gene panel reduced total 3-year costs by 47%, yielding savings exceeding $42.3 billion in an insured panel of 10 million patients. Importantly, 89% of these savings are generated by averting specific adverse events and, thus, optimizing choice of therapy in function of both safety and efficacy.