Akinsanya, Joshua G

INTRODUCTION Heart failure (HF) is characterized by reduced exercise capacity resulting from central and peripheral mechanisms. A primary peripheral mechanism is augmented neural feedback (via group III/IV afferents) arising from the locomotor muscles. This enhanced locomotor neural feedback may result from a variety of mechanisms including increased 1) metabo and/or mechanoreceptor expression, 2) metabolite production, and/or 3) mechano/metaboreceptor sensitivity. Previous studies have shown elevated expression of purinergic 2X3 (P2X3) and cyclooxygenase (COX‐2) in HF compared to sham animal models. However, it is unknown if metabo and/or mechanoreceptor (e.g., Piezo 1 and 2) expression are elevated in human HF. Further, it is unclear if altered receptor expression is related to the cardiovascular and ventilatory responses during exercise attributed to locomotor neural afferent feedback. The purpose of this study was to 1) determine if differences exist in the expression of skeletal muscle proteins associated with metabo/mechanoreflex activity between healthy individuals (CTL) and HF patients and 2) determine relationships between protein expression and the change in ventilatory and cardiovascular responses with locomotor muscle afferent inhibition during exercise. We hypothesized that 1) HF patients will demonstrate greater skeletal muscle protein expression associated with mechano/metaboreflex activity and 2) the increased protein expression will be associated with changes in ventilation, mean arterial pressure (MAP), and catecholamines during locomotor muscle afferent feedback inhibition in HF patients. METHODS In a randomized, placebo controlled cross‐over design, 10 CTL and 6 systolic HF (Age: 60±12 vs. 60±4 yrs, p=0.96; BMI: 26±3 vs. 31±5 kg/m 2 , p=0.01, respectively) patients completed cycling exercise at 60%VO 2 peak with lumbar intrathecal fentanyl or sham. Arterial blood pressure and catecholamines were measured via radial artery catheter during exercise. On a follow up visit, a muscle biopsy from the vastus lateralis was performed to isolate and measure COX‐2, P2X3, transient receptor potential vanilloid type 1 (TRPV1), Piezo 1, and Piezo 2 protein expression. RESULTS Protein expression of P2X3, COX‐2, and TRPV1 were greater in HF compared to CTL (all, p<0.05), with no difference between groups in Piezo 1 and 2 protein expression (p>0.05). HF compared to CTL had a greater decrease in ventilation with fentanyl compared to sham (−11±8 vs. −3±9%, p=0.04, respectively), with no difference between groups in MAP or norepinephrine (p>0.05). In HF, COX expression was negatively related to the change in ventilation (r= −0.87, p=0.02), MAP (r= −0.93, p<0.01), and norepinephrine (r= −0.85, p=0.03) with fentanyl. CONCLUSIONS These data demonstrate that metaborecptors (i.e. P2X3, COX‐2, and TRPV1) are elevated in HF compared to CTL. Furthermore, protein expression of COX‐2 was related to the cardiovascular and ventilatory changes observed with fentanyl in HF patients. These findings suggest that elevated expression of metaboreflex associated proteins contribute to the augmented locomotor muscle afferent feedback during exercise in HF. Support or Funding Information NHLBI RO1 HL126638 AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

New Findings What is the central question of this study? How do locomotor muscle metabo‐ and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase‐2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure. AbstractHeart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo‐ and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase‐2 (COX‐2), purinergic 2X3 (P2X3), transient receptor potential vanilloid type 1 (TRPV1), acid‐sensing ion channel 3 (ASIC3), Piezo 1 and Piezo 2 protein expression. TRPV1 and COX‐2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X3, ASIC3, and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX‐2 protein expression was related to the percentage change in ventilation (r = −0.66) and mean arterial pressure (MAP) (r = −0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRPV1 protein expression was related to the percentage change in systolic blood pressure (r = −0.77, P = 0.02) and MAP (r = −0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRPV1 and COX‐2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRPV1 and COX‐2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF.