When Ventilation Fails to Reflect Disease: Obesity and the Limits of V. _E ‐V. <scp> CO ₂ </scp> Slope for Physiological and Prognostic Interpretation

The recent analysis of the FRIEND registry by Bissen et al. provides a valuable large-scale assessment of the relationship between obesity and ventilatory responses during exercise. The authors report a statistically significant yet negligible association between BMI and the V̇E-V̇CO2 slope in apparently healthy adults [1]. We agree with this interpretation; however, we suggest that the small effect observed may reflect not only a true physiological effect, but also intrinsic limitations of the V̇E-V̇CO2 slope when applied to mechanically constrained phenotypes. A central assumption of the V̇E-V̇CO2 slope is that ventilatory output faithfully reflects the integrated effects of neural drive, gas exchange, and ventilatory control. In obesity, however, this assumption may be weakened [2]. Well-established mechanical constraints—including reduced functional residual capacity, decreased expiratory reserve volume, and increased airway resistance—can limit the capacity to increase ventilation during exercise [2]. Under these conditions, ventilatory output may underrepresent the underlying neural drive, such that a normal or even reduced slope does not necessarily indicate preserved ventilatory efficiency. Importantly, this interpretation should be framed with physiological nuance. Neural drive remains a primary determinant of ventilation, but its external expression may be mechanically constrained. Similarly, the limited expansion of inspiratory capacity observed in individuals with higher BMI should be interpreted in the context of reduced resting operating lung volumes, rather than assumed to reflect dynamic hyperinflation alone [3, 4]. This distinction is relevant because low resting lung volumes may mask the extent of mechanical limitation during exercise. The negligible differences reported by Bissen et al. (e.g., ≈0.4 units between BMI subgroups) are particularly informative. Rather than indicating absence of physiological impact, they may reflect the inability of a linear descriptor to capture heterogeneous ventilatory behavior across exercise intensities. In the present study, the V̇E-V̇CO2 slope was calculated from exercise onset to peak using a single linear regression. However, ventilation does not increase linearly throughout exercise. Distinct physiological phases—rest-to-steady state, post-ventilatory threshold, and respiratory compensation—are governed by different mechanisms, including metabolic acidosis, chemoreflex activation, and progressive mechanical constraint. Previous work has demonstrated that the interpretation of the V̇E-V̇CO2 slope depends on the exercise domain over which it is calculated, with alternative approaches focusing on submaximal segments or the respiratory compensation point [5]. Thus, comparisons across studies—and interpretations within large datasets—should consider that slopes derived from different domains are not physiologically equivalent. These considerations are particularly relevant for clinical interpretation. The prognostic value of the V̇E-V̇CO2 slope is well established in cardiovascular disease, especially in heart failure populations, where obesity is highly prevalent. If mechanical constraints limit the expression of ventilatory demand, the slope may underestimate physiological impairment and attenuate prognostic sensitivity in such populations [2, 6]. Taken together, the findings of Bissen et al. should be interpreted not as evidence that obesity has minimal physiological impact on ventilatory efficiency, but rather as an indication that conventional metrics may incompletely capture ventilatory behavior under mechanical constraint. This reinforces the need for alternative frameworks that integrate ventilatory drive, gas exchange, and ventilatory capacity. One such approach, based on the semi-logarithmic relationship between V̇CO2 and log-transformed ventilation and scaled to an individualized ventilatory capacity ceiling, has been proposed to address these limitations. By focusing on post first ventilatory threshold dynamics and normalizing performance relative to a physiologically defined reference, this framework may provide a more coherent representation of ventilatory efficiency and its clinical implications [7]. In summary, obesity likely exerts a meaningful—but mechanistically complex—impact on ventilatory efficiency and its prognostic interpretation. Recognizing the dissociation between ventilatory drive and ventilatory output in this context is essential to avoid underestimation of disease severity and misclassification of risk. The author has nothing to report. The author has nothing to report. The author declares no conflicts of interest. There is no new data generated.