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Item The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk(Elsevier, 2019) Imboden, Mary T.; Harber, Matthew P.; Whaley, Mitchell H.; Finch, W. Holmes; Bishop, Derron L.; Fleenor, Bradley S.; Kaminsky, Leonard A.; Medicine, School of MedicineBackground The relationship between cardiorespiratory fitness (CRF) and mortality risk has typically been assessed using a single measurement, though some evidence suggests the change in CRF over time influences risk. This evidence is predominantly based on studies using estimated CRF (CRFe). The strength of this relationship using change in directly measured CRF over time in apparently healthy men and women is not well understood. Purpose To examine the association of change in CRF over time, measured using cardiopulmonary exercise testing (CPX), with all-cause and disease-specific mortality and to compare baseline and subsequent CRF measurements as predictors of all-cause mortality. Methods Participants included 833 apparently healthy men and women (42.9 ± 10.8 years) who underwent two maximal CPXs, the second CPX being ≥1 year following the baseline assessment (mean 8.6 years, range 1.0 to 40.3 years). Participants were followed for up to 17.7 (SD 11.8) years for all-cause-, cardiovascular disease- (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (CPX1) peak oxygen consumption (VO2peak [mL·kg−1·min−1]) – visit 2 (CPX2) VO2peak, and mortality outcomes. A Wald-Chi square test of equality was used to compare the strength of CPX1 to CPX2 VO2peak in predicting mortality. Results During follow-up, 172 participants died. Overall, the change in CPX-CRF was inversely related to all-cause, CVD, and cancer mortality (p < 0.05). Each 1 mL·kg−1·min−1 increase was associated with a ~11, 15, and 16% (all p < 0.001) reduction in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality was significant (p < 0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO2peak, and age. Further, the Wald Chi-square test of equality found CPX2 VO2peak to be a significantly stronger predictor of all-cause mortality than CPX1 VO2peak (p < 0.05). Conclusion The change in CRF over time was inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent test than CPX1 CRF. These findings emphasize the importance of adopting lifestyle behaviors that promote CRF, as well as support the need for routine assessment of CRF in clinical practice to better assess risk.Item Exercise Training Improves Cardiac and Skeletal Muscle Metabolism in Rats with Pulmonary Arterial Hypertension(Office of the Vice Chancellor for Research, 2013-04-05) Gaidoo, Richard G.; Crist, Jacob; Little, Nathaniel; Chingombe, Tsungai J.; Fisher, Amanda; Presson, Robert G.; Lahm, Tim; Petrache, Irina; Brown, Mary BethIn patients with pulmonary arterial hypertension (PAH), a shift from oxidative to glycolytic metabolism promotes right ventricular (RV) and skeletal muscle dysfunction that contributes to reduced exercise tolerance. As seen for other cardiopulmonary diseases, exercise training (ExT) may ameliorate this glycolytic switch in PAH and improve exercise capacity. The purpose of this research is to investigate ExT in a rat model of PAH on markers of glycolytic and oxidative metabolism in RV and skeletal muscle. Male Sprague-Dawley rats received monocrotaline (MCT, 40 mg/kg, s.q.) to induce PAH (n= 13), or saline, for healthy controls (n=5). After 2 wks, with MCT-induced PAH established, 6 wks of treadmill (TM) ExT was initiated for a subset of PAH animals (PAH-ExT, n= 6) and healthy controls (CON-ExT, n=3). ExT runs progressed up to 60 min at mild relative intensity, 50% of maximal aerobic capacity (VO2max). VO2max was assessed at baseline, in pre-training and post-training TM testing via analysis of expired gases. Abundance of Glut-1, a marker of glycolytic metabolism, was evaluated in cryosections of RV and soleus with immunofluorescent (IF) staining and quantification. Data are presented as mean±SE. MCT-ExT rats maintained aerobic capacity over 6 wks better than sedentary counterparts (MCT-SED)(VO2max= -134±109 vs. -521±129 ml/kg/hr, p=0.04) and was not different than CON-ExT (-201±31 ml/kg/hr, p=0.82). A lower abundance of Glut-1 was observed in both RV and soleus myocytes of PAH-ExT rats (MPI= 10.9 ±0.9 for RV; 13.7±0.8 for soleus) compared to PAH-SED rats (15.7±2.4, p=0.05, for RV; 17.4±1.4, p=0.04, for soleus) and was similar to CON-ExT rats (13.0±2.2, p=0.33, for RV; 9.0±2.3, p=0.26, for soleus), indicative of a shift toward greater dependency on oxidative metabolism. Exercise training attenuates functional decline following MCT administration in rats. Preservation of aerobic capacity may be explained by promotion of more efficient RV and skeletal muscle mitochondrial substrate utilization.Item A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study(SAGE, 2017-12-04) Brown, Mary Beth; Kempf, Attie; Collins, Catherine M.; Long, Gary M.; Owens, Matthew; Gupta, Shikha; Hellman, Yaron; Wong, Vincent; Farber, Mark; Lahm, Tim; Physical Therapy, School of Health and Rehabilitation SciencesCurrent evidence suggests that exercise training is beneficial in pulmonary arterial hypertension (PAH). Unfortunately, the standard supervised, hospital-based programs limit patient accessibility to this important intervention. Our proof-of-concept study aimed to provide insight into the usefulness of a prescribed walking regimen along with arginine supplementation to improve outcomes for patients with PAH. Twelve PAH patients (all women) in New York Heart Association (NYHA) functional class (FC) II (n = 7) or III (n = 5) and in stable condition for ≥ 3 months were enrolled. Patients performed home- and fitness-center- based walking at 65–75% heart rate (HR) reserve for 45 min, six sessions/week for 12 weeks. Concomitant L-arginine supplementation (6000 mg/day) was provided to maximize beneficial endothelial training adaptations. Cardiopulmonary exercise testing, 6-min walk testing (6MWT), echocardiography, laboratory studies, and quality of life (QoL) survey (SF-36) were performed at baseline and 12 weeks. Eleven patients completed the study (72 session adherence rate = 96 ± 3%). Objective improvement was demonstrated by the 6MWT distance (increased by 40 ± 13 m, P = 0.01), VO2max (increased by 2 ± 0.7 mL/kg/min, P = 0.02), time-to-VO2max (increased by 2.5 ± 0.6 min, P = 0.001), VO2 at anaerobic threshold (increased by 1.3 ± 0.5 mL/kg/min, P = 0.04), HR recovery (reduced by 68 ± 23% in slope, P = 0.01), and SF-36 subscales of Physical Functioning and Energy/Fatigue (increased by 70 ± 34% and 74 ± 34%, respectively, P < 0.05). No adverse events occurred, and right ventricular function and brain natriuretic peptide levels remained stable, suggesting safety of the intervention. This proof-of-concept study indicates that a simple walking regimen with arginine supplementation is a safe and efficacious intervention for clinically stable PAH patients, with gains in objective function and QoL measures. Further investigation in a randomized controlled trial is warranted.