Eric M. Snyder

Arg16Gly polymorphism of the β2‐adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise in humans

In humans, subjects homozygous for arginine (ArgArg) at codon 16 of the β2‐adrenergic receptor (β2AR) have been shown to have greater agonist‐mediated desensitization than subjects homozygous for glycine (GlyGly). We sought to determine if this substitution differentially influenced cardiovascular function during short duration (9 min) low and high intensity exercise (40 and 75% of peak work). Healthy Caucasian ArgArg (n= 16), GlyGly (n= 31) and ArgGly (n= 17) subjects matched for age, sex and peak oxygen uptake were studied. There were no differences in adrenaline (ADR) at rest or with heavy exercise, but the ArgArg group had lower ADR with light exercise (P= 0.04). Resting heart rate (HR) was higher in ArgArg (P < 0.01), while cardiac output , stroke volume (SV), and mean arterial pressure (MAP) were lower than the other groups for ArgArg, ArgGly and GlyGly, respectively, means ±s.e.m., P < 0.01), however, no differences were observed in systemic vascular resistance (SVR). With low intensity exercise and high intensity exercise the ArgArg group continued to have a lower , SV and MAP compared to the other groups (P < 0.05), with no differences observed in SVR. During recovery, the ArgArg subjects continued to have a lower MAP but there were no differences in HR, , or SVR. These data suggest that subjects homozygous for Arg at codon 16 of the β2AR have reduced and MAP at rest that persist during exercise with no evidence for differential changes over the course of exercise despite large changes in catecholamines. This may suggest possible genotype‐related differences in baseline receptor function or density which causes phenotypic differences at rest that are sustained during short‐term exercise.

Isovolumic Acceleration Measured by Tissue Doppler Echocardiography Is Preload Independent in Healthy Subjects

Background: Isovolumic acceleration (IVA) as assessed by Tissue Doppler Imaging (TDI) has been proposed as a measure of left ventricular (LV) contractility. IVA is believed to be less dependent on preload than previously proposed estimates. IVA has been measured at different locations, and studies have shown conflicting results. Objectives: We investigated the impact of increased preload on modern echocardiographic estimates of contractility, including IVA performed at different locations, in healthy volunteers. Methods: Seventeen young healthy individuals (male 13, age 31(± 9) years) with no prior history of cardiovascular or metabolic diseases had a Doppler and Tissue Doppler echocardiographic study performed at baseline and after a rapid infusion of 30ml/kg of bodyweight of isotonic saline. Results are given as mean ± standard deviation (SD), differences tested by paired t‐test. Results: Echocardiographic parameters used to determine changes in preload, altered significantly. E/e′ increased both at the lateral (5 ± 1 vs 7 ± 1 P < 0.01) and at the septal side of the annulus (7 ± 2 vs 9 ± 2, P < 0.01). Afterload remained unchanged. IVA was unchanged regardless of the measurement location: in the basal free wall (1.21 ± 0.58 vs 0.98 ± 0.41, not significant (NS)) or in the mitral annulus (1.18 ± 0.56 vs 1.15 ± 0.33, NS). Peak systolic strain, measured at the basal segment of LV septum, increased significantly (15.4 ± 5.0 vs 20.7 ± 5, P < 0.05), while all other measurements for strain or strain rate (SR) remained unchanged. Conclusion: IVA is unchanged following significant increases in preload in healthy subjects, and thus is a potentially useful measure of global LV contractility.

Glycemic Status Affects Cardiopulmonary Exercise Response in Athletes with Type I Diabetes

PURPOSE This study aimed to (a) examine the influence of type I diabetes on the cardiopulmonary exercise response in trained subjects and (b) determine whether glycemic control affects these responses. METHODS The cardiopulmonary responses to maximal incremental cycle ergometry were compared in 12 Ironman triathletes with type I diabetes and 10 age- and sex-matched control subjects without diabetes. Athletes with type I diabetes were then stratified into low- (glycosylated hemoglobin (HbA1c) < 7%, n = 5) and high-HbA1c (HbA1c > 7%, n = 7) groups for comparison. Cardiac output, stroke volume, arterial blood pressure, and calculated systemic vascular resistance along with airway function were measured at rest and during steady-state exercise. RESULTS During peak exercise HR, stroke volume and cardiac output were not different between the groups with and without diabetes; however, forced expiratory flow at 50% of the forced vital capacity was lower in subjects with diabetes (P < 0.05). Within the group with diabetes, HbA1c was lower in the low-HbA1c versus high-HbA1c group (6.5 +/- 0.3 vs 7.8 +/- 0.4, respectively; P < 0.05), but training volume was not different. At rest, the low-HbA1c group had greater cardiac output and lower systemic vascular resistance than the high-HbA1c group, and all pulmonary function measurements were greater in the low-HbA1c group (P < 0.05). During peak exercise, the VO2, workload, HR, stroke volume, and cardiac output were greater in the low-HbA1c versus the high-HbA1c group (P < 0.05). In addition, all indices of pulmonary function were higher in the low-HbA1c group (P < 0.05). Finally, within the subjects with diabetes, there was a weak inverse correlation between HbA1c and exercise training volume (r2 = -0.352) and stroke volume (r2 = -0.339). These data suggest that highly trained individuals with type I diabetes can achieve the same cardiopulmonary exercise responses as trained subjects without diabetes, but these responses are reduced by poor glycemic control.

Overnight hypoxic exposure and glucagon-like peptide-1 and leptin levels in humans.

Altitude exposure has been associated with loss of appetite and weight loss in healthy humans; however, the endocrine factors that contribute to these changes remain unclear. Leptin and glucagon-like peptide-1 (GLP-1) are peptide hormones that contribute to the regulation of appetite. Leptin increases with hypoxia; however, the influence of hypoxia on GLP-1 has not been studied in animals or humans to date. We sought to determine the influence of normobaric hypoxia on plasma leptin and GLP-1 levels in 25 healthy humans. Subjects ingested a control meal during normoxia and after 17 h of exposure to normobaric hypoxia (fraction of inspired oxygen of 12.5%, simulating approximately 4100 m). Plasma leptin was assessed before the meal, and GLP-1 was assessed premeal, at 20 min postmeal, and at 40 min postmeal. We found that hypoxia caused a significant elevation in plasma leptin levels (normoxia, 4.9 +/- 0.8 pg.mL-1; hypoxia, 7.7 +/- 1.5 pg.mL-1; p < 0.05; range, -16% to 190%), no change in the average GLP-1 response to hypoxia, and only a small trend toward an increase in GLP-1 levels 40 min postmeal (fasting, 15.7 +/- 0.9 vs 15.9 +/- 0.7 pmol.L-1; 20 min postmeal, 21.7 +/- 0.9 vs 21.8 +/- 1.2 pmol.L-1; 40 min postmeal, 19.5 +/- 1.2 vs. 21.0 +/- 1.2 pmol.L-1 for normoxia and hypoxia, respectively; p > 0.05 normoxia vs hypoxia). There was a correlation between SaO2 and leptin after the 17 h exposure (r = 0.45; p < 0.05), but no relation between SaO2 and GLP-1. These data confirm that leptin increases with hypoxic exposure in humans. Further study is needed to determine the influence of hypoxia and altitude on GLP-1 levels.

Exercise-disordered breathing in chronic heart failure

Patients with heart failure develop various ventilatory abnormalities, including reduced ventilatory reserves, increased ventilatory demands, and high work and cost of breathing. They tend to breathe with a rapid-shallow pattern, have low end-expiratory lung volumes, and may develop rhythmic oscillations in ventilation and tidal volume. These abnormalities likely contribute to exercise limitations and are associated with a worsening prognosis.

Comments on Point: Counterpoint: Hypobaric hypoxia induces/does not induce different responses from normobaric hypoxia.

112:1788-1794, 2012. ; J Appl Physiol Joshua C. Weavil, Peter Bartsch and Charles F. Nelatury Samuel Verges, Patrick Levy, Eric M. Snyder, Bruce D. Johnson, Jonathon L. Stickford, Y. Millet, Benjamin D. Levine, James H. Wessel III, Bernard Wuyam, Renaud Tamisier, MacInnis, Michael S. Koehle, Thomas Rupp, Marc Jubeau, Stephane Perrey, Guillaume Laymon, Jack A. Loeppky, Matiram Pun, Kai Schommer, Mary C. Vagula, Martin J. S. Chapman, Johnny Conkin, Hugo Nespoulet, Darren P. Casey, Bryan J. Taylor, Abigail Olivier Girard, Michael S. Koehle, Jordan A. Guenette, Samuel Verges, Robert F. normobaric hypoxia induces/does not induce different responses from Comments on Point:Counterpoint: Hypobaric hypoxia

Exercise is medicine in cystic fibrosis

Exercise activates adrenergic and purinergic pathways that regulate activity of ion channels on airway epithelia cells and sweat glands. Therefore, we hypothesize that exercise is not only an important therapy for cystic fibrosis (CF) patients by facilitating systemic improvements but, more importantly, that exercise can improve the pathophysiological ion dysregulation at a cellular level, thereby enhancing quality of life in CF.

Dietary sodium restriction and β2‐adrenergic receptor polymorphism modulate cardiovascular function in humans

Dietary Na+ intake influences β2‐adrenergic receptor (β2AR) responsiveness. While receiving a normal Na+ diet (150 mmol day−1), subjects homozygous for glycine at amino acid 16 (Gly16) have greater forearm β2AR‐mediated vasodilatation than subjects homozygous for arginine (Arg16), an effect that is mediated by endothelial NO. We tested the hypothesis that dietary Na+ restriction eliminates genotype differences in forearm and systemic β2AR‐mediated dilatation in these groups. We measured heart rate, mean arterial pressure and cardiac output (CO, acetylene breathing) responses to administration of intravenous terbutaline (TRB) before and after 5 days of low dietary Na+ intake (10 mmol day−1) in healthy Gly16 (n= 17; age, 31 ± 7 year) and Arg16 homozygotes (n= 15; age, 29 ± 8 year). After the low‐Na+ diet, a catheter was placed in the brachial artery to measure forearm blood flow (FBF, plethysmography) responses to administration of isoprenaline (isoproterenol) before and after NO inhibition with NG‐mono‐methyl‐l‐arginine (l‐NMMA). In the Gly16 group, the low‐Na+ diet decreased baseline CO from 6.4 ± 1.4 to 5.5 ± 1.2 l min−1 (P= 0.003, paired t test), tended to decrease stroke volume from 97.0 ± 20.6 to 86.9 ± 21.7 ml (P= 0.06) and increased peripheral resistance from 1106 ± 246 to 1246 ± 222 dynes s cm−5 (P= 0.02); significant effects of the low‐Na+ diet were not observed in Arg16 subjects. In a repeated measures ANOVA, the responses of all cardiovascular measures to systemic administration of TRB were not influenced by genotype or diet. Additionally, the FBF response to incremenetal doses of isoprenaline did not differ between genotype groups before or after administration of l‐NMMA. We conclude that dietary Na+ restriction blunted the increased forearm NO‐mediated β2AR responsiveness in Gly16 homozygotes observed in a previous study after normal dietary Na+ intake, while baseline CO decreased and peripheral resistance increased in this group. This study provides evidence that dietary Na+ modulates effects of the Arg16Gly polymorphism on cardiovascular function.

Sex differences in cardiovascular function during submaximal exercise in humans

Differences in cardiovascular function between sexes have been documented at rest and maximal exercise. The purpose of this study was to examine the sex differences in cardiovascular function during submaximal constant-load exercise, which is not well understood.Thirty-one male and 33 female subjects completed nine minutes moderate and nine minutes vigorous intensity submaximal exercise (40 and 75% of peak watts determined by maximal exercise test). Measurements included: intra-arterial blood pressure (SBP and DBP), cardiac index (QI), heart rate (HR), oxygen consumption (VO2) and arterial catecholamines (epinephrine = EPI and norepinephrine = NE), and blood gases. Mean arterial pressure (MAP), stroke volume index (SVI), systemic vascular resistance index (SVRI), arterial oxygen content (CaO2), arterial to venous O2 difference (AVO2) and systemic oxygen transport (SOT) were calculated.At rest and during submaximal exercise QI, SVI, SBP, MAP, NE, CaO2, and SOT were lower in females compared to males. VO2, AVO2, EPI were lower in females throughout exercise. When corrected for wattage, females had a higher Q, HR, SV, VO2 and AVO2 despite lower energy expenditure and higher mechanical efficiency.This study demonstrates sex differences in the cardiovascular response to constant-load submaximal exercise. Specifically, females presented limitations in cardiac performance in which they are unable to compensate for reductions in stroke volume through increases in HR, potentially a consequence of a female’s blunted sympathetic response and higher vasodilatory state. Females demonstrated greater cardiac work needed to meet the same external work demand, and relied on increased peripheral oxygen extraction, lower energy expenditure and improvements in mechanical efficiency as compensatory mechanisms.

Impaired lung diffusing capacity for nitric oxide and alveolar-capillary membrane conductance results in oxygen desaturation during exercise in patients with cystic fibrosis.

BACKGROUND Exercise has been shown to be beneficial for patients with cystic fibrosis (CF), but for some CF patients there is a risk of desaturation, although the predicting factors are not conclusive or reliable. We sought to determine the relationship between the diffusion capacity of the lungs for nitric oxide and carbon monoxide (DLNO and DLCO) and the components of DLCO: alveolar-capillary membrane conductance (D(M)), and pulmonary capillary blood volume (V(C)) on peripheral oxygen saturation (SaO(2)) at rest and during exercise in CF. METHODS 17 mild/moderate CF patients and 17 healthy subjects were recruited (age=26±7 vs. 23±8 years, ht=169±8 vs. 166±8 cm, wt=65±9 vs. 59±8 kg, BMI=23±3 vs. 22±3 kg/m(2), VO(2PEAK)=101±36 vs. 55±25%pred., FEV(1)=92±22 vs. 68±25%pred., for healthy and CF, respectively, mean±SD, VO(2PEAK) and FEV(1) p<0.001). Subjects performed incremental cycle ergometry to exhaustion with continuous monitoring of SaO(2) and measures of DLNO, DLCO, D(M) and V(C) at each stage. RESULTS CF patients had a lower SaO(2) at rest and peak exercise (rest=98±1 vs. 96±1%, peak=97±2 vs. 93±5%, for healthy and CF, respectively, p<0.01). At rest, DLNO, DLCO, D(M) were significantly lower in the CF group (p<0.01). The difference between groups was augmented with exercise (DLNO=117±4 vs. 73±3ml/min/mmHg; DLCO=34±8 vs. 23±8ml/min/mmHg; D(M)=50±1 vs. 34±1, p<0.001, for healthy and CF respectively). Peak SaO(2) was related to resting DLNO in CF patients (r=0.65, p=0.003). CONCLUSIONS These results suggest a limitation in exercise-mediated increases in membrane conductance in CF which may contribute to a drop in SaO(2) and that resting DLNO can account for a large portion of the variability in SaO(2).