The Association Between the Long-Term Change in Directly Measured Cardiorespiratory Fitness and Mortality Risk

Introduction: There is a strong inverse association between cardiorespiratory fitness (CRF) and mortality outcomes. This relationship has predominantly been assessed cross-sectionally, however low CRF is a modifiable risk factor, thus assessing this association using a single baseline measure may be sub-optimal. Purpose: To examine the association of the long-term change in CRF, measured using cardiopulmonary exercise testing (CPX) with all-cause and disease-specific 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. Participants were followed for 17.7 ± 11.8 years for allcause, 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 (V1) peak oxygen consumption (VO2peak (ml·kg-1·min-1)) – visit 2 (V2) VO2peak, and mortality outcomes. Results: During follow-up, 172 participants died. Overall, the change in CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality (p\u3c0.05). Each 1 ml·kg-1·min-1 increase was associated with a 10.8, 14.7, and 15.9% reductions in allcause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality remained significant (p\u3c0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO2peak, and age. Conclusion: Long-term changes in CRF were inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent examination than baseline CRF. These findings support the recent American Heart Association scientific statement advocating CRF as a clinical vital sign that should be assessed routinely in clinical practice, as well as support regular participation in physical activity to maintain adequate CRF levels across the lifespan

The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk

Background: 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 \u3c 0.05). Each 1 mL·kg−1·min−1 increase was associated with a ~11, 15, and 16% (all p \u3c 0.001) reduction in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality was significant (p \u3c 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 \u3c 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

Cardiorespiratory Fitness and Mortality in Healthy Men and Women

Background There is a well-established inverse relationship between cardiorespiratory fitness (CRF) and mortality. However, this relationship has almost exclusively been studied using estimated CRF. Objectives This study aimed to assess the association of directly measured CRF, obtained using cardiopulmonary exercise (CPX) testing with all-cause, cardiovascular disease (CVD), and cancer mortality in apparently healthy men and women. Methods Participants included 4,137 self-referred apparently healthy adults (2,326 men, 1,811 women; mean age: 42.8 ± 12.2 years) who underwent CPX testing to determine baseline CRF. Participants were followed for 24.2 ± 11.7 years (1.1 to 49.3 years) for mortality. Cox-proportional hazard models were performed to determine the relationship of CRF (ml·kg-1·min-1) and CRF level (low, moderate, and high) with mortality outcomes. Results During follow-up, 727 participants died (524 men, 203 women). CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality. Low CRF was associated with higher risk for all-cause (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.20 to 3.50), CVD (HR: 2.27; 95% CI: 1.20 to 3.49), and cancer (HR: 2.07; 95% CI: 1.18 to 3.36) mortality compared with high CRF. Further, each metabolic equivalent increment increase in CRF was associated with a 11.6%, 16.1%, and 14.0% reductions in all-cause, CVD, and cancer mortality, respectively. Conclusions Given the prognostic ability of CPX-derived CRF for all-cause and disease-specific mortality outcomes, its use should be highly considered for apparently healthy populations as it may help to improve the efficacy of the individualized patient risk assessment and guide clinical decisions

The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk

Background 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

Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination

Developmental axon remodeling is characterized by the selective removal of branches from axon arbors. The mechanisms that underlie such branch loss are largely unknown. Additionally, how neuronal resources are specifically assigned to the branches of remodeling arbors is not understood. Here we show that axon branch loss at the developing mouse neuromuscular junction is mediated by branch-specific microtubule severing, which results in local disassembly of the microtubule cytoskeleton and loss of axonal transport in branches that will subsequently dismantle. Accordingly, pharmacological microtubule stabilization delays neuromuscular synapse elimination. This branch-specific disassembly of the cytoskeleton appears to be mediated by the microtubule-severing enzyme spastin, which is dysfunctional in some forms of upper motor neuron disease. Our results demonstrate a physiological role for a neurodegeneration-associated modulator of the cytoskeleton, reveal unexpected cell biology of branch-specific axon plasticity and underscore the mechanistic similarities of axon loss in development and disease

Alterations in Z-line thickness following fast motoneuron transplantation onto slow twitch skeletal muscle fibers

Differentiation of skeletal muscle fibers into fast and slow twitch appears to be under control of the stimulation pattern imparted by motoneurons innervating these muscle fibers. Fast twitch muscle fibers receive intense stimulation for brief periods of time while slow twitch muscle fibers receive less intense stimulation for much longer periods of time. This study examined thickness of Zlines in dually innervated skeletal muscle fibers of slow twitch soleus muscle following transplantation of the fast extensor digitorum longus (EDL) nerve onto the surface of the soleus. Eight individual dually innervated fibers were dissected from four transplanted mouse soleus muscles and examined with a transmission electron microscope. Z-lines in these dually innervated fibers were thinner (mean = 83 nm) than control soleus (mean = 123 nm) and thicker than control EDL (mean = 57 nm). A significant difference (p< .002) was also found between Z-line thickness near the foreign EDL endplate (mean = 81 nm) versus the original soleus endplate (mean = 85 nm). These results suggest the factors controlling protein synthesis in skeletal muscle fibers have both a global and localized effect.Thesis (M.S.)Department of Physiology and Health Scienc

Cardiorespiratory Fitness Measured from Cardiopulmonary Exercise Testing for Mortality Risk Prediction in Apparently Healthy Men and Women

Over the past three decades numerous studies have illustrated the inverse relationship between cardiorespiratory fitness (CRF) and mortality. However, this relationship has almost exclusively been studied using estimated CRF (CRFe), with known error of ± 3 to 7 ml/kg/min, with no studies assessing this association using directly measured CRF in both men and women that were apparently healthy at baseline testing