Muscle metaboreflex stimulates the cardiac sympathetic afferent reflex causing positive feedback amplification of sympathetic activity: effect of heart failure

Abstract

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O₂ delivery and O₂ demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity.NEW & NOTEWORTHY The powerful pressor responses from the CSAR arise via O₂ delivery versus O₂ demand imbalance. Muscle metaboreflex activation (MMA) simultaneously elicits coronary vasoconstriction (which is augmented in heart failure) and profound increases in cardiac work thereby upsetting oxygen balance. Whether MMA activates the CSAR thereby amplifying MMA responses is unknown. We observed that removal of the CSAR afferents attenuated the strength of the muscle metaboreflex in normal and subjects with heart failure.

Keywords: TRPV1; cardiac sympathetic afferents; exercise; exercise pressor reflex; resiniferatoxin.

Figure 1.

A: confocal images showing immunofluorescence double labeling for PGP9.5 (nerve terminal marker, red) and TRPV1 receptors (green) in the left ventricle of one animal (scale bars: 40 µm). Tissue samples from nontreated and RTX-treated (9 wk post-RTX epicardial application) animals in heart failure. B, left: heart rate (HR) and mean arterial pressure (MAP) responses to epicardial capsaicin administration in one animal before (gray) and after application of epicardial RTX (red) during the same surgical procedure. Right: heart rate and mean arterial pressure responses to epicardial capsaicin during a terminal procedure approximately 9 wk post-RTX administration in heart failure. n = 4 animals. RTX, resiniferatoxin.

Figure 2.

Left and middle: linear regressions of averaged hemodynamic responses at rest, threshold, and maximal muscle metaboreflex activation before (black, n = 5) and after application of RTX (red n = 5) in both control and heart failure animals. Figures should be read right to left where the right-most point is free flow exercise, the middle point is the threshold reduction in hindlimb blood flow required to initiate muscle metaboreflex activation, and the furthest left point is peak muscle metaboreflex activation. Right: average muscle metaboreflex gain values in CSAR-intact animals (gray) and CSAR-afferent ablated animals (red) before (open bars) and after induction of heart failure (striped bars) (n = 5 intact, 5 ablated). CSAR, cardiac sympathetic afferent reflex; RTX, resiniferatoxin.