Carotid chemoreceptor ablation improves survival in heart failure: rescuing autonomic control of cardiorespiratory function

Rodrigo Del Rio, Noah J Marcus, Harold D Schultz, Rodrigo Del Rio, Noah J Marcus, Harold D Schultz

Abstract

Objectives: This study sought to investigate whether selective ablation of the carotid body (CB) chemoreceptors improves cardiorespiratory control and survival during heart failure.

Background: Chronic heart failure (CHF) is a recognized health problem worldwide, and novel treatments are needed to better improve life quality and decrease mortality. Enhanced carotid chemoreflex drive from the CB is thought to contribute significantly to autonomic dysfunction, abnormal breathing patterns, and increased mortality in heart failure.

Methods: Chronic heart failure was induced by coronary ligation in rats. Selective CB denervation was performed to remove carotid chemoreflex drive in the CHF state (16 weeks post-myocardial infarction). Indexes of autonomic and respiratory function were assessed in CB intact and CB denervated animals. CB denervation at 2 weeks post-myocardial infarction was performed to evaluate whether early targeted CB ablation decreases the progression of left ventricular dysfunction, cardiac remodeling, and arrhythmic episodes and improves survival.

Results: The CHF rats developed increased CB chemoreflex drive and chronic central pre-sympathetic neuronal activation, increased indexes of elevated sympathetic outflow, increased breathing variability and apnea incidence, and desensitization of the baroreflex. Selective CB ablation reduced the central pre-sympathetic neuronal activation by 40%, normalized indexes of sympathetic outflow and baroreflex sensitivity, and reduced the incidence of apneas in CHF animals from 16.8 ± 1.8 events/h to 8.0 ± 1.4 events/h. Remarkably, when CB ablation was performed early, cardiac remodeling, deterioration of left ventricle ejection fraction, and cardiac arrhythmias were reduced. Most importantly, the rats that underwent early CB ablation exhibited an 85% survival rate compared with 45% survival in CHF rats without the intervention.

Conclusions: Carotid chemoreceptors play a seminal role in the pathogenesis of heart failure, and their targeted ablation might be of therapeutic value to reduce cardiorespiratory dysfunction and improve survival during CHF.

Keywords: CAL; CB; CBD; CHF; EF; Fos-related antigen 1; Fra-1; HRV; IVS; LV; RVLM; autonomic function; breathing disorders; carotid body; carotid body denervation; chronic heart failure; coronary artery ligation; eCBD; early carotid body denervation; ejection fraction; heart failure; heart rate variability; interventricular septum; left ventricle/ventricular; mortality; rostral ventrolateral medulla.

Conflict of interest statement

Disclosures: The authors and have no conflict of interest to disclosure regarding funding or compensation from industry for this study. However, all authors collectively provided consultancy to Coridea NCI (now Cibiem, Inc.) regarding their interests in the efficacy of this procedure in animal models of CHF.

Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Chemoreflex function and selective carotid…
Figure 1. Chemoreflex function and selective carotid body denervation in CHF
(A) Representative ventilatory recordings of the chemoreflex ventilatory response to acute hypoxia (FiO2 ~ 10%) in rats with and without CBD. (B) CBD abrogated the exaggerated hypoxic ventilatory response in CHF rats. VE: minute ventilation. *P<.05 vs. Sham, ***P<.001 vs. Sham, ++P<.01 vs. CHF, +++P<.001 vs. CHF. (Comparisons between groups at same FiO2.) Sham/Sham+CBD, n=6; CHF/CHF+CBD, n=8.
Figure 2. Selective CBD restored normal breathing…
Figure 2. Selective CBD restored normal breathing control in CHF
(A) Representative tracings of tidal volume (Vt) and arterial blood pressure (BP) taken at rest in a Sham and CHF rat before and after CBD. Breathing instability is shown in the Vt tracings from the CHF rat, and CBD restored normal breathing rhythm. (B) Poincare plots showing the breath-to-breath (BB) interval variability in the same rats illustrated in panel A. CBD reduced breathing variability in the CHF rat. (C) and (D) CBD reduced SD1 (short-term variability) and SD2 (long-term variability) of the breathing interval in CHF rats . **P<.01 vs. Sham, ***P<.001 vs. Sham, ++P<.01 vs. CHF; +++P<.001 vs. CHF (E) CBD suppressed the apnea-hypopnea incidence (AHI) in CHF rats. ***P<.001 vs. Sham, ++P<.01 vs. CHF. Sham/Sham+CBD, n=6; CHF/CHF+CBD, n=8.
Figure 3. Selective CBD normalized cardiac autonomic…
Figure 3. Selective CBD normalized cardiac autonomic balance in CHF
(A) Representative traces of the power spectral density (PSD) of heart rate variability (HRV) in Sham, Sham+CBD, CHF and CHF+CBD rats. CHF rats displayed a marked increase in the low frequency (LF) component of the PSD and a decrease in the high frequency (HF) component. (B) CBD markedly reduced low frequency/high frequency ratio (LF/HF) in CHF rats. (C) The LF band expressed in normalized units (n.u.) and (D) the HF band expressed in n.u. *P<.05 vs. Sham, +P< .05 vs. CHF. Sample size as in Fig. 3.
Figure 4. Selective CBD reduced pre-sympathetic neuron…
Figure 4. Selective CBD reduced pre-sympathetic neuron activation in CHF
(A) The number of activated catecholaminergic neurons (arrow, yellow) in the RVLM were increased in CHF rats and reduced in CHF-CBD rats. Note that not all tyrosine hydroxylase (TH) positive cells (green) displayed Fra-1 immunostaining (arrowhead). Individual neurons are shown by nuclear stain, dapi (blue), catecholaminergic neurons by TH expression (green), and activated neurons by Fra-1 expression (red). Activated catecholaminergic neurons (co-expressing TH and Fra-1, yellow) were identified by merging color images. (B) Expression of Fra-1 protein in RVLM micropunches. All lanes were run on the same blot. (C) Quantitative analysis of Fra-1 expression. CBD significantly reduced Fra-1 expression in pre-sympathetic neurons from CHF rats as shown in panel A. βactin protein served as the gel loading control. ***P<.001 vs. Sham, +++P< .001 vs. CHF. n = 6 rats/group.
Figure 5. Early CBD (eCBD) reduced cardiac…
Figure 5. Early CBD (eCBD) reduced cardiac fibrosis in CHF
(A) Rats with CHF and with CHF+eCBD displayed left ventricle (LV) dilation and tissue fibrosis in the infarcted region at 16 weeks post-infarct. (B) Marked collagen deposition was evident in the LV free wall and the interventricular septum (IVS) from CHF. Selective eCBD significantly reduced cardiac fibrosis in the LV-free wall (B–C) and in the IVS (B–D). ***P<.01 vs. Sham, +++P<.001 vs. CHF. n=4 rats/group.
Figure 6. Early CBD reduced arrhythmic episodes…
Figure 6. Early CBD reduced arrhythmic episodes in CHF
(A) Tracings show arrhythmic episodes in a CHF rat and a marked decreased in the arrhythmic events in a CHF+eCBD rat. (B) Arrhythmia incidence was increased in CHF and significantly reversed by eCBD at 16 weeks post CAL. *P<.05 vs. Sham, +P<.05 vs. CHF. n=4 rats/group.
Figure 7. Early CBD delayed cardiac deterioration…
Figure 7. Early CBD delayed cardiac deterioration and improved survival in CHF
(A) Selective eCBD blunted the deterioration in the EF during CHF (expressed as % of the EF values obtained at 2 weeks post-CAL surgery prior to CBD). +P<.01 vs. CHF. (B) Early CBD improved survival rate in CHF rats compared to those with intact CBs (P=.04).

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