In chronic HF outpatients followed for a median of 9.25 years, LVEF and VE/VCO2 at AT were both found to be significant independent predictors of increased risk of CV mortality or HF hospitalization. LVEF was a poor predictor in patients with ventilatory inefficiency and in those with LVEF > 40%. Although our study showed that the interaction effect between LVEF and VE/VCO2 at AT was not significant, the prognostic predictability of LVEF was decreased in the HF with reduced LVEF (HFrEF, LVEF ≤ 39%) population in the ventilatory inefficiency group. As demonstrated in the CHARM Program , the relationship between LVEF and CV outcomes is not linear. We also demonstrated a similar finding in chronic HF outpatients. This relationship was further diminished in the ventilatory inefficiency group. This phenomenon revealed that HF with preserve LVEF (HFpEF, LVEF ≥ 50%) patients who had ventilatory inefficiency had similar CV outcomes as that of their HFrEF counterpart.
This study showed that the ventilation efficiency variable, in addition to LVEF, was a significant prognostic predictor in HF outpatients. Ventilatory inefficiency reflects the adverse effects of HF on lung mechanics and diffusion capacity . An HF also augments ventilatory drive and increases hemodynamic demand associated with breathing work . Ergoreceptors stimulate ventilation and activate sympathetic hormones in response to work. The ergoreflex in the muscle also affects ventilatory effort. In response to carbon dioxide and pulmonary J receptors (which likely respond to congestion and alveolar stiffness), central and pulmonary chemoreceptors contribute to the ergoreflex and result in excess ventilation . In HF patients, a high ventilatory drive can reduce the partial pressure of CO2 (PaCO2) . Consequently, a reduced PaCO2 and increased fractional dead space cause abnormally high VE/VCO2 at AT, i.e., ventilatory inefficiency [18, 19].
The mechanism of ventilatory inefficiency influences the outcomes of HF patients differently between the HFrEF and HFpEF patients. A study analyzed the ventilatory inefficiency between 24 HFrEF patients and 33 HFpEF patients . It demonstrated the loss of cardiac output augmentation related to ventilatory inefficiency regardless of LVEF; however, lung congestion parameters (echocardiographic parameter: e’ and E/e’) correlated with ventilatory inefficiency only in HFpEF. In another study, ventilatory inefficiency appears to be influenced by mechanisms regulating PaCO2 in HFrEF. In contrast, dead space to tidal volume ratio (VD/VT) plays a more important role in developing ventilatory inefficiency in HFpEF . HFpEF and HFrEF may be two distinct entities in terms of ventilatory response to exercise; this study provides evidence that ventilatory inefficiency plays a critical role in HFpEF.
CPET-based measurements of ventilatory inefficiency provide unique physiologic information clinically relevant to contemporary treatment for HF. Several therapeutic interventions for HF affect ventilatory abnormalities both at rest and during exercise. For example, ACEI improves pulmonary diffusion, removes interstitial fluid, and improves pulmonary hemodynamic status . Carvedilol, but not bisoprolol, improves ventilatory efficiency during exercise (reduction of VE/VCO2 slope and increase in maximum end-tidal CO2 pressure) . Carvedilol may have direct effects on respiratory chemoreceptor activity based on the CARNEBI trial . As ventilatory inefficiency is a significant prognostic predictor across the spectrum of LVEF, we should consider ventilatory abnormalities during exercise as therapeutic targets and treat them accordingly. Therapeutic interventions such as rehabilitation training (isolated quadriceps training) , device-guided paced breathing , yoga mantras , and reduction of afferent stimuli from ergopulmonary and cardiopulmonary receptors [28, 29] might all alleviate ventilatory inefficiency. The use of CPET-derived variables to guide therapy and improve outcome deserves further investigation.
This study has some limitations. First, the sample size was relatively small compared to those in other epidemiological studies. However, our study had a longer follow-up period than those of previous works. Second, patients were only recruited from outpatient clinics, which may have caused selection bias. The findings of this study may need further validation in other populations of patients with HF. Third, this study did not analyze other CPET variables that have been used to predict HF outcomes, e.g., oscillatory ventilation, end-tidal CO2 pressure, VO2 kinetics during exercise, oxygen uptake efficiency slope, and heart rate recovery. Therefore, whether the predictive accuracy of these variables can be increased by combining them with VE/VCO2 at AT requires further investigation.