Metaboreceptor activation in heart failure with reduced ejection fraction: Linking cardiac and peripheral vascular haemodynamics

Abstract

We sought to evaluate the muscle metaboreflex in heart failure with reduced ejection fraction (HFrEF) patients, with an emphasis on the interaction between cardiac and peripheral vascular haemodynamics across multiple levels of metaboreceptor activation. In 23 HFrEF patients (63 ± 2 years of age) and 15 healthy control subjects (64 ± 3 years of age), we examined changes in mean arterial pressure, cardiac output, systemic vascular conductance, effective arterial elastance, stroke work and forearm deoxyhaemoglobin concentration during metaboreceptor activation elicited by postexercise circulatory occlusion (PECO) after three levels of static-intermittent handgrip exercise (15, 30 and 45% maximal voluntary contraction). Across workloads, the metaboreflex-induced increase in deoxyhaemoglobin and mean arterial pressure were similar between groups. However, in control subjects, the pressor response was driven by changes (Δ) in cardiac output (Δ495 ± 155, Δ564 ± 156 and Δ666 ± 217 ml min ), whereas this change was accomplished by intensity-dependent reductions in systemic vascular conductance in patients with HFrEF (Δ-4.9 ± 1.5, Δ-9.1 ± 1.9 and Δ-12.7 ± 1.8 ml min mmHg ). This differential response contributed to the exaggerated increases in effective arterial elastance in HFrEF patients compared with control subjects, coupled with a blunted response in stroke work in the HFrEF patients. Together, these findings indicate a preserved role of the metaboreflex-induced pressor response in HFrEF but suggest that this response is governed by changes in the peripheral circulation. The net effect of this response appears to be maladaptive, as it places a substantial haemodynamic load on the left ventricle that may exacerbate left ventricular systolic dysfunction and contribute to exercise intolerance in this patient population.

Clinical safety of blood flow-restricted training? A comprehensive review of altered muscle metaboreflex in cardiovascular disease during ischemic exercise

“…Irrespective of augmented or blunted sympathetic responses to metaboreflex activation, most studies show a preserved BP increase to metaboreflex activation in HF (12,27,122,132). However, as previously reported in animal studies, HF individuals have an impaired capacity to increase SV and CO H95 during metaboreflex activation; thus the metaboreflex-mediated BP increase is largely dependent upon an increase in SVR (12,27,122,132,165).…”

“…Irrespective of augmented or blunted sympathetic responses to metaboreflex activation, most studies show a preserved BP increase to metaboreflex activation in HF (12,27,122,132). However, as previously reported in animal studies, HF individuals have an impaired capacity to increase SV and CO H95 during metaboreflex activation; thus the metaboreflex-mediated BP increase is largely dependent upon an increase in SVR (12,27,122,132,165). Accentuated peripheral vasoconstriction occurs in nonactive vascular beds (122) and in active muscle (3), with the latter reducing skeletal muscle perfusion during exercise, thereby increasing fatigue-related symptoms and stimulating further metaboreflex responses.…”

Autonomic cardiovascular reflex control of hemodynamics during exercise in heart failure with reduced ejection fraction and the effects of exercise training

“…While increased arterial pressure is primarily due to increased cardiac output in health, metaboreflex activation in HFrEF elicits negligible cardiac output changes and thus elevates mean arterial pressure via peripheral vasoconstriction and elevated systemic vascular resistance [63,64,[69][70][71]. A dose-response relationship for this phenomenon was recently reported across three metaboreflex exercise intensities [72]. Cardiac output was limited during metaboreflex activation because of increased coronary vasoconstriction in dogs with HFrEF, but this has yet to be confirmed in humans with HFrEF [73].…”

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

“…In humans, isolation of the metaboreflex (primarily via postexercise circulatory occlusion following forearm exercise) has resulted in preserved and exaggerated blood pressure responses in HFrEF compared to healthy adults (with variable sympathetic nervous system activity responses reported) (Barrett-O'Keefe et al 2018;Carrington et al, 2001;Crisafulli et al 2007;Keller-Ross et al, 2014;Notarius et al, 2001;Piepoli et al 1996Piepoli et al , 1999Shoemaker et al 1998;Silber et al, 1998;Sterns et al, 1991). Despite these discrepancies, it is clear that the contribution of cardiac output and systemic vascular resistance to the metaboreflex-mediated blood pressure response is altered with the HF syndrome (Barrett-O'Keefe et al 2018;Crisafulli et al, 2007;O'Leary et al, 2004). For example, Barrett-O'Keefe et al reported the blood pressure, cardiac output, and systemic vascular resistance responses with isolated metaboreflex activation (via postexercise circulatory occlusion) following forearm exercise at 15%, 30% and 45% maximum voluntary contraction (Barrett-O'Keefe et al, 2018) (see Figure 4).…”