Consequences of group III/IV afferent feedback and respiratory muscle work on exercise tolerance in heart failure with reduced ejection fraction

Abstract

Exercise intolerance and exertional dyspnoea are the cardinal symptoms of heart failure with reduced ejection fraction (HFrEF). In HFrEF, abnormal autonomic and cardiopulmonary responses arising from locomotor muscle group III/IV afferent feedback is one of the primary mechanisms contributing to exercise intolerance. HFrEF patients also have pulmonary system and respiratory muscle abnormalities that impair exercise tolerance. Thus, the primary impetus for this review was to describe the mechanistic consequences of locomotor muscle group III/IV afferent feedback and respiratory muscle work in HFrEF. To address this, we first discuss the abnormal autonomic and cardiopulmonary responses mediated by locomotor muscle afferent feedback in HFrEF. Next, we outline how respiratory muscle work impairs exercise tolerance in HFrEF through its effects on locomotor muscle O₂ delivery. We then discuss the direct and indirect evidence supporting an interaction between locomotor muscle group III/IV afferent feedback and respiratory muscle work during exercise in HFrEF. Last, we outline future research directions related to locomotor and respiratory muscle abnormalities to progress the field forward in understanding the pathophysiology of exercise intolerance in HFrEF. NEW FINDINGS: What is the topic of this review? This review is focused on understanding the role that locomotor muscle group III/IV afferent feedback and respiratory muscle work play in the pathophysiology of exercise intolerance in patients with heart failure. What advances does it highlight? This review proposes that the concomitant effects of locomotor muscle afferent feedback and respiratory muscle work worsen exercise tolerance and exacerbate exertional dyspnoea in patients with heart failure.

Keywords: diaphragm; exercise pressor reflex; metaboreflex; respiratory muscle blood flow.

FIGURE 1

Ventilatory response in HFrEF and its impact on mortality. (a) The ventilation to carbon dioxide (${\dot{V}}_{\mathrm{E}}/\phantom{{\dot{V}}_{\mathrm{E}}{\dot{V}}_{{\mathrm{CO}}_2}}{\dot{V}}_{{\mathrm{CO}}_2}$) slope for a representative healthy control adult and HFrEF patient during incremental exercise. (b) The impact of slope for a representative healthy control adult and HFrEF patient during incremental exercise. (b) The impact of slope on mortality. A higher slope on mortality. A higher slope (i.e., ≥32.65 in this study) was significantly associated with lower survival compared to a lower ${\dot{V}}_{\mathrm{E}}/\phantom{{\dot{V}}_{\mathrm{E}}{\dot{V}}_{{\mathrm{CO}}_2}}{\dot{V}}_{{\mathrm{CO}}_2}$ slope (<32.65) in patients with HFrEF. Data used with permission and adapted from Guazzi et al. (2005).

FIGURE 2

Impact of lower lumbar intrathecal fentanyl on ${\dot{V}}_{{\mathrm{O}}_2\mathrm{peak}}$ in HFrEF patients. ${\dot{V}}_{{\mathrm{O}}_2\mathrm{peak}}$ was 15% higher with fentanyl compared to placebo in patients with HFrEF. *Significantly different from placebo condition. Data used with permission and adapted from Smith, Joyner et al. (2020).

FIGURE 3

Changes in cardiovascular responses with lower lumbar intrathecal fentanyl compared to placebo at ${\dot{V}}_{{\mathrm{O}}_2\mathrm{peak}}$ in controls and HFrEF patients. Percentage changes in cardiac output (${\dot{Q}}_{\mathrm{TOT}}$, a), stroke volume (SV, b), systemic vascular resistance (SVR, c), mean arterial pressure (MAP, d), leg vascular conductance (LVC, e), and leg blood flow (${\dot{Q}}_{\mathrm{L}}$, f) with fentanyl compared to placebo at ${\dot{V}}_{{\mathrm{O}}_2\mathrm{peak}}$ in healthy controls (blue bars) and HFrEF patients (red bars). Cardiac output, stroke volume and leg blood flow were higher with fentanyl than placebo in HFrEF patients. Controls and HFrEF patients had significant decreases in mean arterial pressure and systemic vascular resistance as well as increases in leg vascular conductance with fentanyl. The percentage change in cardiac output, stroke volume and systemic vascular resistance with fentanyl compared to placebo was greater in HFrEF than control. *Significantly different from placebo. †Significantly different from the healthy controls. Data used with permission and adapted from Smith, Joyner et al. (2020).

FIGURE 4

Cardiovascular responses to metaboreflex activation in controls and HFrEF patients. Mean arterial pressure (MAP, a), cardiac output (${\dot{Q}}_{\mathrm{TOT}}$, b), and systemic vascular resistance (SVR, c) with isolated metaboreflex activation (via post‐exercise circulatory occlusion) following forearm exercise at 15%, 30% and 45% maximum voluntary contraction (MVC) in healthy controls (blue bars) and HFrEF patients (red bars). Controls and HFrEF patients had similar increases in mean arterial pressure with isolated metaboreflex activation. The controls increased mean arterial pressure via increases in cardiac output with metaboreflex activation. In contrast, HFrEF patients increased mean arterial pressure by increases in systemic vascular resistance. *Significantly different compared to rest. Data used with permission and adapted from Barrett‐O'Keefe et al. 2018).

FIGURE 5

Impact of respiratory muscle unloading on submaximal exercise tolerance in HFrEF. In HFrEF patients, respiratory muscle unloading resulted in an ∼50% increase in exercise time (i.e., time‐to‐task failure) during constant workload cycling at ∼75% peak workload. *Significantly different from the control condition. Data used with permission and adapted from Borghi‐Silva et al. (2008).

FIGURE 6

Changes in cardiovascular responses with respiratory muscle unloading during submaximal exercise in controls and HFrEF patients. Percentage changes in work of breathing (W _b, a), cardiac output (${\dot{Q}}_{\mathrm{TOT}}$, b), stroke volume (SV, c), leg vascular resistance (LVR, d), leg blood flow (${\dot{Q}}_{\mathrm{L}}$, e), and leg blood flow (as a percentage of cardiac output) (f) with respiratory muscle unloading in healthy controls (blue bars) and HFrEF patients (red bars). Respiratory muscle unloading resulted in significant reductions in the work of breathing in controls and HFrEF patients. With respiratory muscle unloading, cardiac output, stroke volume, leg blood flow and leg blood flow (as a percentage of cardiac output) increased, and leg vascular resistance decreased in HFrEF patients. *Significantly different from the control condition. †Significantly different from the healthy controls. Data used with permission and adapted from Olson et al. (2010).

FIGURE 7

Potential consequences between locomotor muscle afferent feedback and respiratory muscle work in HFrEF during exercise. (a) Summary of the locomotor muscle group III/IV afferent feedback and respiratory muscle work mediated abnormal autonomic and cardiopulmonary responses in HFrEF patients during exercise outlined in this review. (b) Illustration of potential autonomic and cardiopulmonary interactions between locomotor muscle afferent feedback and respiratory muscle work in HFrEF, and the subsequent impact on locomotor muscle O₂ delivery and exercise tolerance.