BACKGROUND AND AIMS
Dyspnoea and exercise intolerance are near universal symptoms in fibrotic interstitial lung disease (fILD).1 Neither anti-fibrotic agents approved for the treatment of idiopathic pulmonary fibrosis significantly diminished exertional dyspnoea.2 The physiological mechanisms of dyspnoea and exercise intolerance in fILD are poorly understood. In other chronic diseases, such as chronic obstructive pulmonary disease and chronic heart failure, there is emerging evidence that the sensitivity of metabolically responsive skeletal muscle afferents (muscle metaboreflex) is augmented.3,4 This can contribute to exercise intolerance through dyspnoea, exaggerated sympathetic vasoconstriction, and hypoperfusion of the active muscle.5 The authors hypothesised that muscle metaboreflex sensitivity is augmented in fILD and drives dyspnoea.
MATERIALS AND METHODS
Thirteen patients with fibrotic fILD (two female; 70±13 years; forced vital capacity [FVC]: 72±19% predicted; forced expiratory volume in 1 second [FEV1]/FVC: ≥0.7; fibrosis on high-resolution CT) and 15 healthy controls (four female; 68±7 years) were recruited. In a randomised crossover design, participants completed 2 minutes of rhythmic handgrip (50% maximal voluntary contraction) followed by either:
i) two minutes of post-exercise circulatory occlusion (PECO trial), where a cuff placed around the upper arm was inflated to a supra-systolic pressure preventing the removal of chemical by-products of exercise, to isolate muscle metaboreflex activation; or
ii) rested for 4 minutes (control trial).
Minute ventilation (VE), mean arterial pressure (MAP), and heart rate (HR) were measured and analysed using two-way analysis of variance. Muscle metaboreflex sensitivity was calculated as the intra-individual difference in physiological response between the last 90 seconds of the PECO trial and the corresponding period in the control trial. Dyspnoea intensity was measured with a 0–10 Borg scale.6 Comparisons between the healthy and fILD groups were assessed using a Student’s unpaired t-test.
The majority of patients with fILD had a diagnosis of idiopathic pulmonary fibrosis (n=5). Other diagnoses were connective tissue disease-associated interstitial lung disease (n=3), interstitial pneumonia with autoimmune features (n=1), organising pneumonia (n=1), unclassifiable (n=2), and asbestosis (n=1). There were no significant differences in terms of age, height, weight, or maximum voluntary contraction between the healthy and fILD groups. The fILD group had lower predicted FEV1 (p=0.00), FVC (72±19% versus 107±8%; p=0.00), and higher FEV1/FVC (p=0.02) compared with healthy controls. Exercise increased VE, MAP, and HR (p<0.05) in all groups. VE and MAP remained elevated during PECO (p<0.05) with no differences between groups. There was no difference in muscle metaboreflex sensitivity for the MAP, VE, or HR responses between the groups (e.g., ΔVE: fILD 0.01±1.5 L/min versus healthy 0.35±1.6 L/min; p=0.55). In the patients with fILD, PECO did not increase the mean dyspnoea rating relative to control (1.3±1.3 units versus 1.0±1.2 units; p=0.19).
These findings suggest that skeletal muscle metaboreflex sensitivity is not augmented in fILD. Metaboreflex activation did not result in increased dyspnoea. The contribution of other sensory afferents should be explored in the investigation of the mechanisms underlying dyspnoea and exercise intolerance in fILD.