What is the clinical significance of VO2 (maximal oxygen uptake) max in adults, particularly those with a history of cardiovascular disease or risk factors?

Clinical Significance of VO2 Max

VO2 max is the single best measure of cardiovascular fitness and exercise capacity, and serves as a powerful independent predictor of all-cause mortality and cardiovascular disease risk. 1

Fundamental Definition and Measurement

VO2 max represents the peak oxygen uptake achieved during dynamic exercise involving large muscle groups. 1 By strict definition, it is the point where oxygen consumption plateaus despite increasing workload, though most patients—particularly those with cardiovascular disease—cannot achieve this plateau due to leg fatigue, symptoms, or cardiac limitations. 1 In clinical practice, the term "peak VO2" more accurately describes the highest oxygen uptake attained during volitional incremental exercise. 1

VO2 max equals the product of maximum cardiac output and maximum arteriovenous oxygen difference, making it a comprehensive measure of the entire oxygen delivery and utilization system. 1 The oxygen pulse (VO2 max divided by peak heart rate) provides valid inferences about forward stroke volume at peak exercise, since arteriovenous oxygen difference reaches a physiological limit across most cardiovascular conditions. 1

Prognostic Significance for Mortality

Even modest increases of ≥2 mL/kg/min to levels ≥12 mL/kg/min in severe heart failure patients predict 100% 2-year survival. 2 This demonstrates that small incremental gains carry profound prognostic significance.

The established prognostic thresholds include:

• VO2 max <14 mL/kg/min identifies heart failure patients requiring transplant consideration, with one-year survival of only 70% in accepted transplant candidates versus 94% in those above this threshold. 1, 2
• **VO2 max <10 mL/kg/min represents the highest-risk category**, particularly when combined with a VE/VCO2 slope >40. 1
• VO2 max <10.4 mL/kg/min in pulmonary arterial hypertension predicts 50% one-year survival versus 91% above this threshold. 2

Previous meta-analyses demonstrate that increases in VO2 max of 1.75–3.5 mL/kg/min are associated with lower risk of all-cause mortality and incidence of coronary heart disease or cardiovascular disease. 1 This means systematic and random errors in estimation beyond 3.5 mL/kg/min will miss clinically relevant changes.

Cardiovascular Risk Stratification

In healthy populations, individuals below median VO2 max (<35.1 mL/kg/min in women, <44.2 mL/kg/min in men) have 5-8 times higher odds of cardiovascular risk factor clustering compared to the highest quartile. 3 Each 5 mL/kg/min lower VO2 max corresponds to approximately 56% higher odds of cardiovascular risk factor clustering. 3

Longitudinal increases in VO2 max from adolescence to age 36 are associated with less arterial stiffness, particularly in muscular arteries, independent of other risk factors. 4 This relationship is mediated by concomitant changes in HDL cholesterol and body weight in elastic arteries. 4

Assessment in Heart Failure

Peak VO2 determination during maximal symptom-limited exercise testing is the most objective method to assess exercise capacity in heart failure patients (ACC/AHA Class IIa recommendation). 1 It surpasses subjective measures like NYHA functional class and the 6-minute walk test, which cannot estimate how close patients are to maximal capacity. 1

The VE/VCO2 slope (ventilatory efficiency) has been found by multiple investigators to be even more predictive of outcome than peak VO2, with the advantage of not requiring maximal effort. 1 The most commonly cited threshold is a VE/VCO2 slope of 34, with mortality risk increasing progressively as the slope increases from normal (≤30) to ≥40. 1

Heart failure patients with peak VO2 <10 mL/kg/min or VE/VCO2 slope >40 should be considered highest-risk, and those with both characteristics have particularly poor prognosis. 1

Factors Affecting VO2 Max

VO2 max is influenced by multiple factors:

• Age: Maximum values occur between ages 15-30 years, declining progressively with age at 3-6% per decade in younger individuals, accelerating to >20% per decade in older age groups. 1
• Cardiovascular disease: Pre-existing LV dysfunction or exercise-induced myocardial ischemia greatly affects VO2 max, as do symptoms requiring test termination (angina, hypertension, dysrhythmia). 1
• Sex, exercise habits, and heredity all contribute to baseline values. 1

Training Response and Improvement Potential

Exercise training consistently increases VO2 max by 12-31% across various protocols, with most improvements occurring within the first 3 weeks but continuing up to 6 months with sustained compliance. 2 In chronic heart failure patients, similar improvements (12-31%) correlate with increased muscle mitochondria and decreased ventilation. 2

Measurement Considerations

Consumer wearables using exercise tests provide systematic error close to zero (-0.09 mL/kg/min) compared to laboratory indirect calorimetry, but random error remains large (±9.83 mL/kg/min). 1 This random error, while smaller than resting-based estimations (±15.24 mL/kg/min), is still substantial for individual-level assessment. 1 The exercise-based algorithms show high accuracy at the group level, enabling digital phenotyping of cardiorespiratory fitness at population levels. 1

Clinical Application Algorithm

For heart failure patients:

1. Measure peak VO2 during symptom-limited exercise testing 1
2. If peak VO2 <10 mL/kg/min → highest risk category, consider advanced therapies 1
3. If peak VO2 10-14 mL/kg/min → evaluate VE/VCO2 slope and consider transplant evaluation 1, 2
4. If peak VO2 ≥14 mL/kg/min → transplantation can be safely deferred 1
5. Monitor for improvements ≥2 mL/kg/min to levels ≥12 mL/kg/min, which predict excellent prognosis 2

Beta-blocker therapy does not alter the prognostic value of peak VO2, though the 14 mL/kg/min transplant cutoff may require re-evaluation in this context. 2