A novel exercise testing algorithm to diagnose mitochondrial myopathy

Abstract

Introduction Oxygen uptake efficiency slope (OUES) is a noninvasive cardiopulmonary exercise testing (CPET) measurement based on oxygen uptake (V˙O2) and minute ventilation (V˙E) and is a marker of the efficiency of oxygen utilization by the body. However, it has not been studied in mitochondrial disorders. We explored noninvasive CPET parameters, including OUES, as a way to reliably diagnose mitochondrial myopathy. Methods We performed cycle ergometer maximal exercise testing on definite and suspected mitochondrial myopathy subjects (MM‐D and MM‐S) and their age‐ and sex‐matched controls. OUES was corrected for body surface area (OUES/BSA) to eliminate the effect of body size. Results A total of 40 participants, including 20 MM‐D (n = 13; 6 males; aged 14‐64 years) and 7 MM‐S (5 males, aged 11‐30 years) subjects and 20 controls, completed the study. MM‐D subjects showed lower aerobic fitness than controls. OUES/BSA was lower in MM‐D subjects, suggesting inefficient oxygen utilization. Area under the curve (AUC) and 95% confidence interval (CI) for OUES/BSA (AUC, 0.91; 95% CI, 0.80‐1.00), peak V˙O2 percent predicted (AUC, 0.95; 95% CI, 0.86‐1.00), and V˙O2/work slope (AUC, 0.94; 95% CI, 0.85‐1.00) showed excellent ability to diagnose mitochondrial myopathy in MM‐D subjects. We applied a diagnostic approach based on the parameters just noted to MM‐S subjects and their controls and were able to support or disprove the diagnosis of mitochondrial myopathy. Discussion We proposed and applied an approach based on the aformentioned three CPET parameters to diagnose mitochondrial myopathy reliably and found it to be clinically useful.

Physiologic responses to exercise in survivors of critical illness: an exploratory pilot study

“…Our finding that the global pattern of exercise responses, which included impaired oxygen utilization, increased ventilation, and hyperdynamic heart rate, parallels CPET findings seen in those with mitochondrial myopathies [8,15,20] also contributes to existing literature regarding physical function after the ICU. Muscle mitochondrial dysfunction occurs early in critical illness and sepsis [21], and it is strongly linked to survival.…”

“…No participants had ventilatory or gas exchange limitations to exercise nor exercise-induced ischemia. Participants did, however, have a pattern of low oxygen pulse, elevated chronotropic index, low VO 2 -work rate slope, and prolonged VO 2 recovery halftime, indicating impaired oxygen utilization with a hyperdynamic heart rate response (Table 2), a physiologic pattern that mirrors responses seen in patients with mitochondrial myopathies [8,15,20]. VO 2 -work rate slope and VO 2 recovery half-time were strongly correlated with both VO 2Peak and 6MWT distance (Figs.…”

“…We also measured oxygen uptake efficiency slope (OUES), an effort-independent measure of exercise capacity that reflects the relationship between oxygen utilization and total ventilation [14]. Lower OUES, in the absence of reduced cardiac output, suggests inefficient oxygen utilization necessitating greater ventilatory effort to meet oxygen demand during exercise [14,15]. We measured two additional parameters of oxygen utilization: VO 2 -work rate slope [16] and VO 2 recovery half-time [17,18].…”

Exercise testing and prescription in patients with inborn errors of muscle energy metabolism

“…This suggests that CPET should be used in conjunction with other diagnostic investigations; or used instead to monitor progress following exercise interventions. Despite these limitations, some variables measured during CPET could be used to establish the suspicion of primary mitochondrial myopathies, although it would warrant further testing 54–56,99,102 …”

“…98 A recent study reported these patients have a lower ratio of oxygen uptake to power output (work) slope, highlighting a reduced ability to utilise oxygen to attain a particular workload compared to control subjects. 54,56,[99][100][101][102][103] Similar to McArdle disease and LC-FAOD, patients with primary mitochondrial myopathies appear to have significantly lower exercise capacity than their healthy peers, though the evidence in children and adolescents remains quite limited (see Table 4). [99][100][101][102] Within the mitochondrial cohort there is very wide variability in exercise capacity, with some patients not meeting the minimum VO 2 threshold for ADLs (15 mL/ kg/min for women, 18 mL/kg/min for men) 2,104 and others achieving VO 2 peak greater than 90% of predicted.…”