RESUMO
PURPOSE: Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF. METHODS: Patients aged 55-80 years with symptoms of heart failure, body mass index ≤ 35 kg/m2, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m2, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e' index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF, n = 9). Patients without heart failure with preserved ejection fraction (non-HFpEF, n = 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O2 and 90% N2, with CO2 titrated) and central chemoreceptors stimulation (7% CO2 and 93% O2) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography. RESULTS: During hypoxia, MSNA responses were greater (p < 0.001) and FBF responses were lower in patients with HFpEF (p = 0.006). Likewise, MSNA responses during hypercapnia were higher (p < 0.001) and forearm vascular conductance (FVC) levels were lower (p = 0.030) in patients with HFpEF. CONCLUSIONS: Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.
RESUMO
AIMS: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (VÌO2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak VÌO2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2 -pulse (VÌO2 × HR-1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak VÌO2 , is inversely associated with the change in peak VÌO2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. METHODS AND RESULTS: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak VÌO2 (%) was analysed as a function of baseline peak VÌO2 and its determinants (absolute peak VÌO2 , peak O2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak VÌO2 through changes in peak O2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (VÌO2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2 -pulse explained approximately 72% of the difference in changes in peak VÌO2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2 -pulse on change in peak VÌO2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2 -pulse was associated with a decreased mean change in peak VÌO2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak VÌO2 (P > 0.05). Change in VÌO2 at VT1 was not associated with any of the investigated factors (P > 0.05). CONCLUSIONS: In patients with HFpEF, the easily measurable peak O2 -pulse seems to be a good indicator of the potential for improving peak VÌO2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2 -pulse, patients with high O2 -pulse may need to use additional therapies to significantly increase peak VÌO2 .