Exercise-Induced Electrocardiography Changes in Pulmonary Arterial Hypertension.

Cardiopulmonary exercise testing (CPET) is an important tool in assessing the functional status of patients with pulmonary arterial hypertension (PAH). During CPET, continuous electrocardiography (ECG) is used as a marker of exercise-induced ischemia or arrhythmia. We hypothesize that ECG changes with exercise may be an early indicator of clinical worsening in PAH and could predict adverse outcomes. Clinical, hemodynamic, and CPET data of 155 children and young adult patients with PAH who underwent CPET between 2012 and 2019 in our pulmonary hypertension (PH) center were included in this retrospective analysis. ECGs were analyzed for ST depressions and T-wave inversions, along with coincident hemodynamic data. These data were correlated with adverse outcomes divided into 2 categories: severe worsening (death or receiving lung transplant) and mild to moderate worsening (PAH medication escalation, hospitalization, shunt creation, or listing for lung transplant). The median age was 19 years (range 7 to 40 years), 69% were female, and the average follow-up time was 5 years (range 1 to 8 years). A total of 63 patients (41%) had at least 1 adverse outcome. A total of 39 patients (25%) demonstrated significant ST-T-wave changes with exercise. Patients with ST-T-wave changes were 20% more likely to die or need lung transplant than those without. The multiple linear regression found that ST-T-wave changes were a predictor of elevated mean pulmonary arterial pressure (mPAP) found on catheterization (R = 0.489, p = 0.003), although not of pulmonary vascular resistance index (R = -0.112, p = 0.484). An mPAP of 55 mm Hg was the most sensitive and specific point in identifying when ST-T-wave changes with exercise begin to appear. In conclusion, ST-T-wave changes on exercise ECG are significantly associated with adverse outcomes in PH in a medium-term follow-up study, and the presence of ST-T-wave changes correlates with higher mPAP. These ECG changes with exercise may be used as early indicators of clinical worsening in PH and predictors of adverse outcomes.

Characterizing the Use of Exercise Testing in Repaired Tetralogy of Fallot Patients: A Multi-Institutional Survey.

Cardiopulmonary exercise testing (CPET) is an important tool used in the management of patients with congenital heart disease. However, there are no clear guidelines for its use in specific populations, such as repaired Tetralogy of Fallot (rTOF). We sought to characterize current practice patterns and attitudes regarding exercise testing in the rTOF population using an online survey distributed to pediatric cardiologists. Analyses were performed using qualitative statistics, Wilcoxon rank-sum, Kruskal-Wallis test, and chi-squared analysis. 103 clinicians completed the survey with 83% routinely sending symptomatic rTOF patients for exercise testing and 59% for asymptomatic patients. Respondents who routinely test asymptomatic patients reported higher levels of perceived helpfulness of exercise testing (p < 0.01) and comfort with CPET interpretation (p < 0.01). Although a large majority of respondents found exercise testing to be helpful (81% either "somewhat" or "very" helpful"), a considerably smaller portion indicated comfort with CPET interpretation (49% either "comfortable" or "very comfortable"). Nearly all respondents (92%) reported changing management primarily based on exercise testing results. However, the frequency of changes varied, with 10% "frequently", 62% "occasionally", 19% "rarely" changing management. There was a statistically significant relationship between the perceived helpfulness of exercise testing and the likelihood of management changes (p < 0.01). While exercise testing is used to make clinical decisions, our findings suggest that in some cases, management changes may be made without a similar degree of confidence in interpreting CPET findings. The variability in attitudes and practices highlights the need for evidence-based guidelines addressing exercise testing in rTOF, particularly for asymptomatic patients.

Characterizing the Use of Exercise Testing in Repaired Tetralogy of Fallot Patients: A Multi-Institutional Survey.

Long-term survival for repaired Tetralogy of Fallot (rTOF) is excellent. We achieve this by close clinical monitoring to stratify prognosis and guide clinical decision-making. Cardiopulmonary exercise stress testing (CPET) is used to help guide clinical decision making; however, there are no clear guidelines for its use in this population. We sought to describe practice variability with regards to exercise testing for rTOF patients and how exercise data is used to guide management. We distributed a survey to pediatric cardiologists via email. Analyses were performed using qualitative statistics, two-sample T-tests, and chi-squared analysis. One-hundred and three clinicians completed the survey with 83% reporting that they routinely send symptomatic rTOF patients for exercise testing and 59% for asymptomatic patients. Respondents who routinely test asymptomatic patients reported higher levels of perceived helpfulness of exercise testing (p = 0.04) and comfort with CPET interpretation (p = 0.03). Nearly all respondents (92%) reported changing management primarily based on exercise testing results, with 62% reporting "occasionally changing management" and 10% reporting "frequently changing management". Results indicated that exercise test results influenced clinical decisions, such as the timing of interventions, need for additional imaging, or the initiation of exercise interventions. There was a statistically significant relationship between the perceived helpfulness of exercise testing and the likelihood of management changes (p < 0.01). The variability in attitudes and practices highlights the need for evidence-based guidelines addressing exercise testing in rTOF, particularly for asymptomatic patients.

ehealth technology in cardiac exercise therapeutics for pediatric patients with congenital and acquired heart conditions: a summary of evidence and future directions.

Many children and adolescents with congenital and acquired heart disease (CHD) are physically inactive and participate in an insufficient amount of moderate-to-vigorous intensity exercise. Although physical activity (PA) and exercise interventions are effective at improving short- and long-term physiological and psychosocial outcomes in youth with CHD, several barriers including resource limitations, financial costs, and knowledge inhibit widespread implementation and dissemination of these beneficial programs. New and developing eHealth, mHealth, and remote monitoring technologies offer a potentially transformative and cost-effective solution to increase access to PA and exercise programs for youth with CHD, yet little has been written on this topic. In this review, a cardiac exercise therapeutics (CET) model is presented as a systematic approach to PA and exercise, with assessment and testing guiding three sequential PA and exercise intervention approaches of progressive intensity and resource requirements: (1) PA and exercise promotion within a clinical setting; (2) unsupervised exercise prescription; and (3) medically supervised fitness training intervention (i.e., cardiac rehabilitation). Using the CET model, the goal of this review is to summarize the current evidence describing the application of novel technologies within CET in populations of children and adolescents with CHD and introduce potential future applications of these technologies with an emphasis on improving equity and access to patients in low-resource settings and underserved communities.

Average Exercise Capacity in Men and Women >75 Years of Age Undergoing a Bruce Protocol Exercise Stress Test.

Exercise stress testing is routinely performed to evaluate suspected coronary artery disease in older adults. However, the available data to predict and compare relative exercise capacity in the general population were developed using predominantly younger, healthy cohorts with few or no women. This study aimed to describe the exercise capacity of patients older than 75 years who underwent a clinically indicated Bruce protocol exercise stress test. This was a retrospective, cross-sectional study of 2,041 consecutive patients older than 75 years who performed a Bruce protocol exercise stress echocardiogram that was terminated because of maximal effort without ischemia at Columbia University Medical Center between April 10, 2009, and July 30, 2020. The analytic sample included 2,041 exercise stress tests in 786 women (median [interquartile range] age 79 [77 to 81] years) and 1,255 men (median [interquartile range] age 79 [77 to 82] years). Cardiovascular risk factors and clinical coronary disease were common and more prevalent in men than women. The median exercise time for men aged 76 to 80 years was 7:22 (minutes:seconds) and for women was 6:00 and significantly decreased in both genders as age increased (p <0.001). The mean (SD) METs achieved for women and men were 6.5 (1.6) and 7.7 (1.7), respectively. Most women (85%) and men (95%) completed the first stage, whereas only 32% of women and 64% of men completed the second stage. It was uncommon for women (3%) or men (15%) to complete the third stage. Fewer than 1% of patients completed the fourth stage, and none completed the fifth stage. At all ages, women had a lower exercise capacity than men. These data allow physicians to compare the exercise capacity of older patients who underwent a Bruce protocol exercise stress test more accurately to a representative sample of similarly aged adults.

Telerehabilitation Using Fitness Application in Patients with Severe Cystic Fibrosis Awaiting Lung Transplant: A Pilot Study.

PURPOSE: The purpose of this study was to pilot a home-based pulmonary rehabilitation (PR) program administered via a telemedicine approach using a combination of fitness application and self-selected activity in lung transplant candidates with cystic fibrosis (CF). METHODS: We recruited adult patients with CF. The main outcome was adherence, measured by number of sessions completed in 12 weeks. Secondary outcomes were adverse events, six-minute walk distance (6MWD), and dyspnea. Participants were provided a personalized exercise program and equipment including a fitness application that provided exercise videos, recorded exercise time, and corresponding heart rate. We reviewed data daily and provided text messages with feedback. We compared our study outcomes to a retrospective data set of CF patients who participated in a 24-session outpatient hospital-based PR program. Data presented as mean ± standard deviation. RESULTS: Eleven patients participated in the home PR program, 45% female, age 33 ± 7 years, FEV1 27 ± 5% predicted. Sessions completed were 19 ± 12 home-based PR vs. 9 ± 4 hospital-based PR, p = .03. Fifty percent of the home-based group completed ≥24 sessions in 12 weeks versus 0% of the hospital-based patients (p = .03). There were no adverse events during exercise. Completers of the home-based program demonstrated a clinically meaningful lower decline in 6 MWD than noncompleters (6MWD -7 ± 15 vs. -86 ± 108 meters). Only one participant performed a post 6 MWD in the hospital-based PR. CONCLUSION: Patients with severe CF demonstrated adherence to home PR delivered using fitness application and self-selected activity with no adverse events. This program style may be a viable solution for telerehabilitation in severe CF and is particularly relevant in the COVID era.

Laboratory Validation of Hexoskin Biometric Shirt at Rest, Submaximal Exercise, and Maximal Exercise While Riding a Stationary Bicycle.

OBJECTIVE: Evaluate Hexoskin performance on a stationary bike against "gold standard" laboratory equipment and develop adjustment models for future use in field settings. METHODS: Compared respiratory rate (RR), tidal volume (VT), minute ventilation (VE), and heart rate (HR) measured by the Hexoskin shirt to simultaneous spirometry and full 12-lead electrocardiogram during a laboratory based incremental exercise test on a stationary bicycle. RESULTS: Data from 17 participants demonstrated Hexoskin VT and VE had the best agreement in the submaximal exercise level (discrepancies less than or equal to 5.3%) with larger discrepancies observed at rest (less than or equal to 15.3%) and at maximal exercise level (less than or equal to 11.7%). The discrepancies for HR and RR were lower at all levels (less than 10%). Adjusting for sex and body weight allowed for a single VE algorithm across the entire range of effort (r = 0.89). CONCLUSION: These discrepancies are acceptable for field use in comparison to the ranges typical of bicycle commuting.

Frailty and maximal exercise capacity in adult lung transplant candidates.

BACKGROUND: Frail lung transplant candidates are more likely to be delisted or die without receiving a transplant. Further knowledge of what frailty represents in this population will assist in developing interventions to prevent frailty from developing. We set out to determine whether frail lung transplant candidates have reduced exercise capacity independent of disease severity and diagnosis. METHODS: Sixty-eight adult lung transplant candidates underwent cardiopulmonary exercise testing (CPET) and a frailty assessment (Fried's Frailty Phenotype (FFP)). Primary outcomes were peak workload and peak aerobic capacity (V˙O2). We used linear regression to adjust for age, gender, diagnosis, and lung allocation score (LAS). RESULTS: The mean ± SD age was 57 ± 11 years, 51% were women, 57% had interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had cystic fibrosis, and the mean LAS was 40.2 (range 19.2-94.5). In adjusted models, peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V˙O2 decreased by 1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V˙O2 was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to non-frail participants. Frailty accounted for 16% of the variance (R2) of watts and 19% of the variance of V˙O2 in adjusted models. CONCLUSION: Frailty contributes to reduced exercise capacity among lung transplant candidates independent of disease severity.

Cardiopulmonary exercise factors predict survival in patients with advanced interstitial lung disease referred for lung transplantation.

BACKGROUND: The purpose of this work was to determine if parameters assessed during Cardiopulmonary Exercise Testing (CPET) while using supplemental oxygen can independently predict one-year transplant-free survival in patients with Interstitial Lung Disease (ILD) referred for lung transplant evaluation. METHODS: We performed a chart review of patients with ILD who completed CPET with 30% FiO2 and gathered spirometry, pulmonary hemodynamic, six-minute walk, and CPET data. The primary end-point was death or lung transplantation within one-year of CPET. RESULTS: The final data set included 192 patients. 79 patients died/underwent transplant, 113 survived transplant-free. Multivariable Cox regression revealed peak workload % predicted, nadir CPET SpO2, and FVC% predicted as independent predictors of one-year transplant-free survival. Of the independent predictors of survival, receiver operating characteristics analysis revealed peak workload %predicted cutoff of 35% to be highly discriminatory, more so than nadir CPET SpO2 or FVC % predicted in identifying patients at risk for one-year mortality or transplant (peak workload % predicted < 35% HR = 4.71, 95% CI = 2.64-8.38 and area under the curve (AUC) = 0.740, nadir CPET SpO2 < 86% HR = 2.27, 95%CI = 1.41-3.68, AUC = 0.645, FVC %predicted <45% HR = 1.82, 95% CI = 1.15-2.87, AUC = 0.624). CONCLUSION: Peak workload % predicted, nadir CPET SpO2, and FVC% predicted in ILD patients referred for lung transplant evaluation are independently predictive of one-year mortality or need for transplant.

Non-invasive measurement of abnormal ventilatory mechanics in amyotrophic lateral sclerosis.

INTRODUCTION: In this study we investigated non-invasive, effort-independent measurement of ventilatory mechanics in patients with amyotrophic lateral sclerosis (ALS). METHODS: Ventilatory mechanics were measured by optoelectronic plethysmography (OEP) in ALS patients and matched controls. Analysis determined whether OEP measurements correlated with standard clinical measures. RESULTS: ALS patients (N = 18) had lower forced vital capacity percent predicted (55.2 ± 22.0 L) compared with controls (N = 15; 104.7 ± 16.2 L) and higher ventilatory inefficiency (49.2 ± 9.0 vs. 40.0 ± 3.5, respectively; P < 0.001 for both measures). Lower tidal volumes within the diaphragm area correlated with the dyspnea subscore calculated from the ALS Functional Rating Scale-revised (P = 0.031), and paradoxical movement of the ribcage compared with the abdominal compartment was seen in the most severe cases. CONCLUSIONS: Evaluation of ventilatory mechanics in mild to severe ALS reveals dysfunction that is not readily detected by standard testing and ALS functional severity assessment measures. Muscle Nerve 54: 270-276, 2016.

Quantification of Improvements in Static and Dynamic Ventilatory Measures Following Lung Volume Reduction Surgery for Severe COPD.

Rationale: This study quantitatively measured the effects of lung volume reduction surgery (LVRS) on spirometry, static and dynamic lung and chest wall volume subdivision mechanics, and cardiopulmonary exercise measures. Methods: Patients with severe COPD (mean FEV1 = 23 ± 6% predicted) undergoing LVRS evaluation were recruited. Spirometry, plethysmography and exercise capacity were obtained within 6 months pre-LVRS and again within 12 months post- LVRS. Ventilatory mechanics were quantified using stationary optoelectronic plethysmography (OEP) during spontaneous tidal breathing and during maximum voluntary ventilation (MVV). Statistical significance was set at P< 0.05. Results:Ten consecutive patients met criteria for LVRS (5 females, 5 males, age: 62±6yrs). Post -LVRS (mean follow up 7 months ± 2 months), the group showed significant improvements in dyspnea scores (pre 4±1 versus post 2 ± 2), peak exercise workload (pre 37± 21 watts versus post 50 ± 27watts ), heart rate (pre 109±19 beats per minutes [bpm] versus post 118±19 bpm), duty cycle (pre 30.8 ± 3.8% versus post 38.0 ± 5.7%), and spirometric measurements (forced expiratory volume in 1 second [FEV1] pre 23 ± 6% versus post 32 ± 13%, total lung capacity / residual lung volume pre 50 ± 8 versus 50 ± 11) . Six to 12 month changes in OEP measurements were observed in an increased percent contribution of the abdomen compartment during tidal breathing (41.2±6.2% versus 44.3±8.9%, P=0.03) and in percent contribution of the pulmonary ribcage compartment during MVV (34.5±10.3 versus 44.9±11.1%, P=0.02). Significant improvements in dynamic hyperinflation during MVV occurred, demonstrated by decreases rather than increases in end expiratory volume (EEV) in the pulmonary ribcage (pre 207.0 ± 288.2 ml versus post -85.0 ± 255.9 ml) and abdominal ribcage compartments (pre 229.1 ± 182.4 ml versus post -17.0 ± 136.2 ml) during the maneuver. Conclusions: Post-LVRS, patients with severe COPD demonstrate significant favorable changes in ventilatory mechanics, during tidal and maximal voluntary breathing. Future work is necessary to determine if these findings are clinically relevant, and extend to other environments such as exercise.

Feasibility and Acceptability of Utilizing a Smartphone Based Application to Monitor Outpatient Discharge Instruction Compliance in Cardiac Disease Patients around Discharge from Hospitalization.

The purpose of this study was to determine the feasibility and acceptability of utilizing a smartphone based application to monitor compliance in patients with cardiac disease around discharge. For 60 days after discharge, patients' medication compliance, physical activity, follow-up care, symptoms, and reading of education material were monitored daily with the application. 16 patients were enrolled in the study (12 males, 4 females, age 55 ± 18 years) during their hospital stay. Five participants were rehospitalized during the study and did not use the application once discharged. Seven participants completed 1-30 days and four patients completed >31 days. For those 11 patients, medication reminders were utilized 37% (1-30-day group) and 53% (>31-day group) of the time, education material was read 44% (1-30) and 53% (>31) of the time, and physical activity was reported 25% (1-30) and 42% (>31) of the time. Findings demonstrated that patients with stable health utilized the application, even if only minimally. Patients with decreased breath sounds by physical exam and who reported their health as fair to poor on the day of discharge were less likely to utilize the application. Acceptability of the application to report health status varied among the stable patients.

Optoelectronic plethysmography compared to spirometry during maximal exercise.

The purpose of this study was to compare simultaneous measurements of tidal volume (Vt) by optoelectronic plethysmography (OEP) and spirometry during a maximal cycling exercise test to quantify possible differences between methods. Vt measured simultaneously by OEP and spirometry was collected during a maximal exercise test in thirty healthy participants. The two methods were compared by linear regression and Bland-Altman analysis at submaximal and maximal exercise. The average difference between the two methods and the mean percentage discrepancy were calculated. Submaximal exercise (SM) and maximal exercise (M) Vt measured by OEP and spirometry had very good correlation, SM R=0.963 (p<0.001), M R=0.982 (p<0.001) and high degree of common variance, SM R(2)=0.928, M R(2)=0.983. Bland-Altman analysis demonstrated that during SM, OEP could measure exercise Vt as much as 0.134 L above and -0.025 L below that of spirometry. OEP could measure exercise Vt as much as 0.188 L above and -0.017 L below that of spirometry. The discrepancy between measurements was -2.0 ± 7.2% at SM and -2.4 ± 3.9% at M. In conclusion, Vt measurements at during exercise by OEP and spirometry are closely correlated and the difference between measurements was insignificant.

The effect of lung volume reduction surgery on chronotropic incompetence.

BACKGROUND: Chronotropic incompetence (CI) is a marker of poor prognosis in patients with COPD. Treatments that improve pulmonary function and exercise capacity may affect CI. Objectives are to evaluate CI before and after lung volume reduction surgery (LVRS) and determine if changes in CI are associated with changes in pulmonary function and exercise capacity. METHODS: We performed a retrospective review of 75 patients who underwent LVRS and who had complete cardiopulmonary exercise testing and concurrent pulmonary function tests two months before and about 6 months after surgery. Additionally we evaluated 28 control patients that were randomized to medical treatment as part of the National Emphysema Treatment Trial at our center. We studied CI using the percent of predicted heart rate reserve=(heart rate peak-heart rate rest)/((208-0.7×age)-heart rate rest)×100, before and after surgery and compared it to the control group. RESULTS: Mean percent of predicted heart rate reserve improved from 41% to 50% (p-value <0.001) after LVRS, while the control group did not change. The mean forced vital capacity and expiratory volume in 1s, peak oxygen consumption, carbon dioxide production, ventilation, tidal volume and maximal workload all improved in the surgery group, while the controls did not improve. CONCLUSIONS: CI improves after LVRS in a population of patients with COPD. CI improvements are associated with the increases in pulmonary function and exercise capacity. This improvement is seen in a domain of known cardiopulmonary impairment prior to surgery that improves as a positive response to the therapy of LVRS.

Evaluation of pulmonary function and exercise performance by cardiopulmonary exercise testing before and after lung transplantation.

BACKGROUND: Detailed description of functional exercise outcomes before and after lung transplantation is lacking. The objective of this study was to describe and compare posttransplant improvement in lung function and peak exercise parameters in patients with advanced lung disease. METHODS: The study included 153 patients who underwent lung transplantation over 7 years who had complete cardiopulmonary exercise testing (CPET) and pulmonary function tests (PFTs) before and after lung transplantation. CPET and PFT within 30 months pretransplant and posttransplant were compared. RESULTS: Pulmonary function markedly improved posttransplant as FVC increased 67%, maximum voluntary ventilation increased 91%, and FEV(1) increased 136%. However, peak oxygen consumption increased only 19%, peak CO(2) production increased 50%, and peak work increased 78%. Although transplant recipients had a 1.5- to 2.0-fold increase in exercise capacity posttransplant, peak exercise capacity remained at 50% of the predicted normal, suggesting a maximal limitation. Subgroup stratification into quartiles based on pretransplant exercise capacity revealed the greatest exercise benefit to be in the lowest functional pretransplant groups. CONCLUSIONS: Lung transplant recipients have an increase in exercise capacity that does not match the improvement in lung function, indicating that poor strength, deconditioning, or other peripheral factors play a significant role in the limitation of exercise benefit posttransplantation. Further elucidation of the mechanisms of exercise limitation may allow for improved exercise outcomes posttransplant.

Exercise ventilatory kinematics in endurance trained and untrained men and women.

To determine how increased ventilatory demand impacts ventilatory kinematics, we compared the total chest wall volume variations (V(CW)) of male and female endurance-trained athletes (ET) to untrained individuals (UT) during exercise. We hypothesized that training and gender would have an effect on V(CW) and kinematics at maximal exercise. Gender and training significantly influenced chest wall kinematics. Female ET did not change chest wall end-expiratory volume (V(CW,ee)) or pulmonary ribcage (V(RCp,ee)) with exercise, while female UT significantly decreased V(CW,ee) and V(RCp,ee) with exercise (p<0.05). Female ET significantly increased pulmonary ribcage end-inspiratory volume (V(RCp,ei)) with exercise (p<0.05), while female UT did not change V(RCp,ei) with exercise. Male ET significantly increased V(RCp,ei) with exercise (p<0.05); male UT did not. Men and women had significantly different variation of V(CW) (p<0.05). Women demonstrated the greatest variation of V(CW) in the pulmonary ribcage compartment (V(RCp)). Men had even volumes variation of the V(RCp) and the abdomen (V(Ab)). In conclusion, gender and training had a significant impact on ventilatory kinematics.

Sympathetic drive is modulated by central chemoreceptor activation.

To determine the effects of central chemoreceptor stimulation upon sympathetic modulation while minimizing baroreceptor influences, we performed a single-blind, counter-balanced, placebo-controlled trial of a modified hypercapnic/hyperoxic rebreathe protocol stimulus to activate the central chemoreflex. Muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, and ventilation were recorded dynamically as subjects transitioned from a hypocapnia to hypercapnia state. The stages of data recording were defined as hyperventilation (HyV), pre-threshold (PreT) and post-threshold (PostT), with threshold being defined as the point of non-linear deviation in ventilation. The changes in MSNA (-4.2+/-52.4 arbitrary units (AU) vs. 245.0+/-84.0AU) and burst count (-0.1+/-0.7 bursts/segment vs. 2.5+/-1.7 bursts/segment) were significantly different between control and rebreathe for the HyV to PreT step. There was also a significant difference for PreT to PostT for total MSNA (3.9+/-65.4AU vs. 183.7+/-104.2AU). In a hypercapnic/hyperoxic state, the central chemoreceptors modulate sympathetic activity below the chemoreflex threshold independently of the baroreceptors, possibly contributing to basal autonomic/sympathetic tone. Central chemoreceptors also appear to play a significant role in sympathetic modulation after the threshold.