Snyder, Eric M.

Abstract Rationale Deficits in infant lung function—including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)—have been linked to increased risk for childhood asthma. Objectives To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life. Methods One hundred eighty participants in the Tucson Children’s Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models. Measurements and Main Results After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% (P = 0.001) and 55% (P = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26. Conclusions These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.

The Beta‐2 adrenergic receptors (β 2 ARs) are located on alveolar cells and the pulmonary lymphatics and regulate lung fluid clearance through activation of epithelial sodium channels on the alveolar cells and through the relaxation of the lymphatic vessels. We sought to determine the influence of an inhaled β 2 ‐selective agonist on alveolar‐capillary conductance (DM) and pulmonary capillary blood volume (Vc) in healthy humans. To determine this, we assessed the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide before and every 15 minutes for one‐hour following the administration of nebulized albuterol (2.5mg, diluted to 3ml) in 28 healthy subjects (age=28±5yrs, ht=171±14cm, wt=75±17kg, BMI=26±8kg/m 2 , values are mean±SD). Cardiac output (Q, determined via acetylene wash‐in), heart rate (HR), stroke volume (SV), systemic vascular resistance (SVR), blood pressure (BP), and oxygen saturation (SaO2) were also assessed at baseline and following the administration of albuterol. Albuterol resulted in elevations in HR, Q, and SV as well as a drop in SVR (% change from baseline, HR=4±11, 4±8, 4±8, and 4±8%; Q=15±17, 12±17, 9±19, and 4±17%; SV= 24±32, 16±27, 11±28, and 14±23%; and SVR= −15±12, −12±16, −7±20, and −4±17, at 15, 30, 45, and 60 minutes post‐albuterol, respectively, P‐ANOVA<0.05), but no change in BP. There was no change in DLCO, a decrease in Vc and an increase in DM when assessed alone or when corrected for Vc (%change from baseline, Vc=5±37, −5±30, −12±35, and −20±26%, DM= 0±18, 1±18, 6±22, and 5±19%; DM/Vc=10±44, 17±48, 47±70, and 48±70%, at 15, 30, 45, and 60 minutes post‐nebulization, respectively, p<0.05). These data suggest that the administration of albuterol improves alveolar‐capillary conductance in healthy humans, despite a small decrease in pulmonary capillary blood volume.

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.

Background: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aβ-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a β-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged β-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. Methods: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C 2 H 2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). Results: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m 2 vs healthy = 1.84 ± 0.04 m 2 , P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m 2 vs healthy = 39.9 ± 2.5 mL/beat/m 2 , P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm −5 vs healthy = 1616 ± 74 dynes*s/cm −5 , P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV ( P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F (2,14) = 7.982, P < .01) and SV index (F (2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). Conclusions: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

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.

Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological, and genetic predictors of cold noxious pain tolerance. Healthy subjects (n = 89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ‐III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold‐pressor test in a 1–2°C water bath for a maximum of 3 minutes. The primary outcome measure was pain tolerance, defined as the maximum duration of time subjects left their nondominant hand in the cold‐water bath. Cox proportional hazards regression indicated that female sex, Asian race, and increasing PCS and FPQ‐III scores were associated with lower pain tolerance. No candidate SNP was significantly associated with pain tolerance. Future genetic studies should include demographic and psychological variables as confounders in experimental pain models.

Cardiac hemodynamic assessment during cardiopulmonary exercise testing (CPET) is proposed to play an important role in the clinical evaluation of individuals with cystic fibrosis (CF). Cardiac catheterization is not practical for routine clinical CPET. Use of oxygen pulse (O 2 pulse) as a noninvasive estimate of stroke volume (SV) has not been validated in CF. This study tested the hypothesis that peak exercise O 2 pulse is a valid estimate of SV in CF. Measurements of SV via the acetylene rebreathe technique were acquired at baseline and peak exercise in 17 mild-to-moderate severity adult CF and 25 age-matched healthy adults. We calculated [Formula: see text]. Baseline relationships between SV and O 2 pulse were significant in CF ( r = .80) and controls ( r = .40), persisting to peak exercise in CF ( r = .63) and controls ( r = .73). The standard error of estimate for O 2 pulse-predicted SV with respect to measured SV was similar at baseline (14.1 vs 20.1 mL) and peak exercise (18.2 vs 13.9 mL) for CF and controls, respectively. These data suggest that peak exercise O 2 pulse is a valid estimate of SV in CF. The ability to noninvasively estimate SV via O 2 pulse during routine clinical CPET can be used to improve test interpretation and advance our understanding of the impact cardiac dysfunction has on exercise intolerance in CF.