Respiratory exchange ratio overshoot during exercise recovery: a promising prognostic marker in HFrEF
Authors: Vecchiato Marco , Neunhaeuserer Daniel , Zanardo Emanuele , Quinto Giulia , Battista Francesca , Aghi Andrea , Palermi Stefano , Babuin Luciano , Tessari Chiara , Guazzi Marco , Gasperetti Andrea , Ermolao Andrea 
Published: February 2024

Abstract
Background and aims
Transient increases (overshoot) in respiratory gas analyses have been observed during exercise recovery, but their clinical significance is not clearly understood. An overshoot phenomenon of the respiratory exchange ratio (RER) is commonly observed during recovery from maximal cardiopulmonary exercise testing (CPET), but it has been found reduced in patients with heart failure with reduced ejection fraction (HFrEF). The aim of the study was to analyze the clinical significance of these RER recovery parameters and to understand if these may improve the risk stratification of patients with HFrEF.

Methods
This cross-sectional study includes HFrEF patients who underwent functional evaluation with maximal CPET for the heart transplant checklist at our Sports and Exercise Medicine Division. RER recovery parameters, including RER overshoot as the percentual increase of RER during recovery (RER mag), have been evaluated after CPET with assessment of hard clinical long-term endpoints (MACEs/deaths and transplant/LVAD-free survival).

Results
A total of 190 patients with HFrEF and 103 controls were included (54.6 ± 11.9 years; 73% male). RER recovery parameters were significantly lower in patients with HFrEF compared to healthy subjects (RER mag 24.8 ± 14.5% vs 31.4 ± 13.0%), and they showed significant correlations with prognostically relevant CPET parameters. Thirty-three patients with HFrEF did not present a RER overshoot, showing worse cardiorespiratory fitness and efficiency when compared with those patients who showed a detectable overshoot (VO2 peak: 11.0 ± 3.1 vs 15.9 ± 5.1 ml/kg/min; VE/VCO2 slope: 41.5 ± 8.7 vs 32.9 ± 7.9; ΔPETCO2: 2.75 ± 1.83 vs 4.45 ± 2.69 mmHg, respectively). The presence of RER overshoot was associated with a lower risk of cardiovascular events and longer transplant-free survival.

Conclusion
RER overshoot represents a meaningful cardiorespiratory index to monitor during exercise gas exchange evaluation; it is an easily detectable parameter that could support clinicians to comprehensively interpreting patients’ functional impairment and prognosis. CPET recovery analyses should be implemented in the clinical decision-making of advanced HF.

Graphical Abstract
RER Overshoot during CPET recovery phase in HFrEF
Transient increases, also called overshoot, in respiratory exchange ratio (RER) have been observed during exercise recovery in healthy subjects and patients with chronic diseases. A total of 190 patients with HFrEF who underwent CPET for heart transplant checklist were analyzed and compared with 103 controls, using a protocol to monitor gas exchange during recovery phase. RER overshoot was significantly lower in patients with HFrEF than controls, and some patients with HFrEF (17.4%) presented no overshoot. The presence of RER overshoot was associated with higher aerobic capacity and cardiorespiratory efficiency with lower risk of cardiovascular events and longer transplant/LVAD-free survival. HFrEF, heart failure with reduced ejection fraction; CPET, cardiopulmonary exercise testing; LVAD, left ventricular ejection fraction.