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
V¿O2peak. 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 V¿O2peak. 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. V¿O2peak, 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 range of chronic disease
states where deconditioning is a common feature.
