Abnormal chemoreflex sensitivity to hypoxia and hypercapnia predictors in chronic heart failure

Abstract

Background: Increased chemoreflex sensitivity to hypoxia and/or hypercapnia holds a prognostic value in chronic heart failure (HF), whereas its direct measurement is not widely applied, mainly due to technical constraints, We therefore aimed to evaluate whether/which clinical features, easily obtainable as part of current patient investigation, may predict altered chemoreflex sensitivity. Methods: We recruited 191 chronic patients with systolic HF (83% male, age 62±14, left ventricular ejection fraction –LVEF- 30±8%, NYHA class I-II/III: 72/28%) on optimal medical therapy. All patients underwent thorough clinical and neurohormonal evaluation, including echocardiography, cardiorespiratory monitoring and cardiopulmonary exercise testing (CPET), as well as hypoxic-normocapnic and hypercapnic-normoxic chemoreflex sensitivity evaluation by standard rebreathing technique. Variables associated with altered chemoreflex sensitivity were assessed with univariate logistic regression analysis and, due to the reduced number of events with respect to the number of variables selected, with Bayesian Model Averaging (BMA) for the estimation of multivariate models. Correlates of chemoreflex sensitivity were also assessed by random forests analysis, based on iterative computational statistics. Results: After univariate logistic regression and BMA, altered hypoxic chemoreflex sensitivity was associated with the presence of Cheyne Stokes respiration (CSR) and with the slope of ventilation to carbon dioxide production (VE/VCO2) at CPET; hypercapnic chemoreflex sensitivity was associated with VE/VCO2, LVEF, N-terminal fragment of brain natriuretic peptide (NT-proBNP) and ACE-inhibitor therapy, as a protective variable. At random forests analysis VE/VCO2 and NT-proBNP showed the strongest association with hypercapnic chemoreflex sensitivity, while CSR and VE/VCO2 showed the strongest association with hypoxic chemoreflex sensitivity. Conclusions: Reduced ventilatory efficiency predicts increased chemoreflex sensitivity to either hypoxia and hypercapnia. Altered peripheral chemoreflex is predicted by the presence of CSR, too, while abnormal central chemonsensitivityis associated with LV systolic dysfunction and neurohormonal activation. In clinical grounds, the assessment of these easily obtainable variables could help identify patients with altered chemoreflex sensitivity and thus selecting subsets suitable for targeted interventions