Muscle metaboreflex-induced vasoconstriction in the ischemic active muscle is exaggerated in heart failure

Abstract

When oxygen delivery to active muscle is insufficient to meet the metabolic demand during exercise, metabolites accumulate and stimulate skeletal muscle afferents, inducing a reflex increase in blood pressure, termed the muscle metaboreflex. In healthy individuals, muscle metaboreflex activation (MMA) during submaximal exercise increases arterial pressure primarily via an increase in cardiac output (CO), as little peripheral vasoconstriction occurs. This increase in CO partially restores blood flow to ischemic muscle. However, we recently demonstrated that MMA induces sympathetic vasoconstriction in ischemic active muscle, limiting the ability of the metaboreflex to restore blood flow. In heart failure (HF), increases in CO are limited, and metaboreflex-induced pressor responses occur predominantly via peripheral vasoconstriction. In the present study, we tested the hypothesis that vasoconstriction of ischemic active muscle is exaggerated in HF. Changes in hindlimb vascular resistance [femoral arterial pressure ÷ hindlimb blood flow (HLBF)] were observed during MMA (via graded reductions in HLBF) during mild exercise with and without α-adrenergic blockade (prazosin, 50 µg/kg) before and after induction of HF. In normal animals, initial HLBF reductions caused metabolic vasodilation, while reductions below the metaboreflex threshold elicited reflex vasoconstriction, in ischemic active skeletal muscle, which was abolished after α-adrenergic blockade. Metaboreflex-induced vasoconstriction of ischemic active muscle was exaggerated after induction of HF. This heightened vasoconstriction impairs the ability of the metaboreflex to restore blood flow to ischemic muscle in HF and may contribute to the exercise intolerance observed in these patients. We conclude that sympathetically mediated vasoconstriction of ischemic active muscle during MMA is exaggerated in HF. NEW & NOTEWORTHY We found that muscle metaboreflex-induced vasoconstriction of the ischemic active skeletal muscle from which the reflex originates is exaggerated in heart failure. This results in heightened metaboreflex activation, which further amplifies the reflex-induced vasoconstriction of the ischemic active skeletal muscle and contributes to exercise intolerance in patients.

Exercise intolerance and fatigue in chronic heart failure: is there a role for group III/IV afferent feedback?

“…SVR increase) in the mechanisms by which the target blood pressure is reached during EPR. It is to be considered that this hemodynamic scenario closely resembles what has been also reported in animal models of CHF [70][71][72] .…”

Acute and chronic exercise in patients with heart failure with reduced ejection fraction: evidence of structural and functional plasticity and intact angiogenic signalling in skeletal muscle

“… b ; Kaur et al . ) and, typically, those patients with the greatest SNA have the poorest chance of survival (Cohn et al . ).…”

“…Neurohumoral activation, including increased sympathetic nervous system activity (SNA), is a hallmark characteristic of advanced HFrEF (Esposito et al 2010b;Kaur et al 2018) and, typically, those patients with the greatest SNA have the poorest chance of survival (Cohn et al 1984). So strong is this link that almost every pharmacological intervention proven to increase survival in HFrEF interrupts this increase in SNA (Packer et al 2001).…”

“…; Kaur et al . ), decreased capillary‐to‐fibre ratio, reduced capillary density and smaller capillary diameter (Duscha et al . ; Piepoli et al .…”

“…Although heart failure with reduced ejection fraction (HFrEF) is fundamentally a disease that impacts central haemodynamics, a variety of skeletal muscle alterations, including muscle atrophy, a shift in fibre type, impaired oxidative capacity, reduced mitochondrial enzymes and decreased mitochondrial volume density, are typically associated with this pathology (Mancini et al 1992;Harrington et al 1997;Esposito et al 2010bEsposito et al , 2015Kaur et al 2018;Poole et al 2018). In terms of the peripheral vasculature, HFrEF has also been linked to autonomic and cardiovascular dysregulation that leads to greater sympathetic vasoconstrictor tone (Magnusson et al 1997;Kaur et al 2018), decreased capillary-to-fibre ratio, reduced capillary density and smaller capillary diameter (Duscha et al 1999;Piepoli et al 2010a,b;Esposito et al 2010b;Poole et al 2012). These findings imply that in addition to the inability of the heart to appropriately raise pumping capacity during exercise, both skeletal muscle and the peripheral vasculature also contribute to the exercise intolerance associated with HFrEF, a hallmark of this pathology.…”