PROJECT SUMMARY Cardiopulmonary exercise testing (CPET) is an objective, non-invasive, measure of the integrated function of the pulmonary, cardiovascular and neuromuscular systems. CPET evaluates submaximal and peak exercise responses, informing on causes of dyspnea and/or fatigue, disease prognosis and/or progression, pre- or post- surgical risk stratification, or exercise training prescription. Clinical use of CPET is estimated to have increased by 81% between 2005 and 2015. The most common problem for CPET interpretation is discriminating between cardiovascular disease and neuromuscular deconditioning e.g., low muscle mass, weakness and/or fatigability. We have developed a solution to this problem, using a modified CPET with integrated isokinetic (IK) measurements of muscle power, which independently assesses neuromuscular performance without affecting measurement of standard CPET variables. The modified CPET adds <10min to the standard CPET and uses commercially available equipment. The modified CPET produces 4 new IK variables: 1) Baseline peak isokinetic power: deconditioned muscles are weak; 2) Tolerance index: the fraction of peak IK power at V̇O2peak. Aerobic deconditioning reduces the available peak IK power that can be supported by aerobic metabolism; 3) Fatigue index: The loss of peak IK power for a given work rate. Aerobic deconditioning increases fatigability; 4) Power reserve: The capacity for acute power increase at V̇O2peak. A power reserve indicates that neuromuscular performance is not limiting to exercise tolerance. The modified CPET is reproducible and well tolerated by elderly, normal subjects and athletes, and those with heart failure or COPD. The modified CPET can differentiate neuromuscular deconditioning as a cause of exercise limitation from cardiovascular or pulmonary limitations (assessed by standard CPET). To inform clinical interpretation, this project will develop predictive models describing normal reference values for IK variables in men and women aged 18-80yr. Threshold values of neuromuscular performance (with corresponding sensitivity and specificity) will be developed and optimized to discriminate a deconditioned population. Variables that moderate neuromuscular performance measures associated with deconditioning will be identified (e.g. V̇O2peak, diastolic dysfunction, vascular reactivity, leg lean mass, leg strength and power, muscle oxidative capacity and muscle biopsy morphology). Finally, the discriminative ability of IK variables for deconditioning will be tested by measuring sensitivity of IK variables in response to exercise training in deconditioned individuals and the specificity of IK variables to discriminate peripheral vs. central hemodynamic exercise limitations using invasive CPET in patients with heart failure and preserved ejection fraction. This study will transform the utility and diagnostic capabilities of CPET and improve clinical decision-making and severity stratification across a wide...