Carotid Body-Mediated Chemoreflex Drive in The Setting of low and High Output Heart Failure

Figures

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  Figure 1. Rats with myocardial infarction (MI-CHF) and arteriovenous fistula (AV-CHF) have similar degrees of cardiac hypertrophy. (A) Representative images of hearts obtained in one Sham rat, one rat with MI-CHF and one rat with AV-CHF. Note the large ventricular dilation in both MI-CHF and AV-CHF vs. Sham condition. (B) Cardiac hypertrophy (heart weight/body weight [HW/BW]) was evident in both MI-CHF and AV-CHF rats compared to Sham rats. *p < 0.05 vs. Sham condition, Sidak post-hoc test after one-way ANOVA, n = 6 rats.

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  Figure 2. Carotid artery blood flow in low output and high output heart failure. (A) Representative traces of carotid artery blood flow, assessed by Doppler at rest in one Sham rat, one MI-CHF rat and one AV-CHF rat. (B) Summary data showing carotid artery blood flow. Note that blood flow to the CB region was significantly reduced in MI-CHF vs. Sham. Also note that AV-CHF rats display similar blood flow values compared to Sham rats. *p < 0.05 vs. Sham; +p < 0.05 vs. AV-CHF condition, Sidak post-hoc test after one-way ANOVA, n = 6 rats.

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  Figure 3. Carotid body-mediated chemoreflex function in heart failure rats. The hypoxic ventilatory response was increased in MI-CHF rats compared to Sham condition. However, in AV-CHF the peripheral chemoreflex ventilatory response to acute hypoxic stimulation was blunted. ***p < 0.001 vs. Sham; *p < 0.05 vs. Sham; +p < 0.001 vs. AV-CHF; and +p < 0.05 vs. AV-CHF, Sidak post-hoc test after one-way ANOVA, n = 6 rats.

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  Figure 4. Myocardial infarction (MI-CHF) and arteriovenous fistula (AV-CHF) rats display autonomic imbalance. (A) The total power of heart rate variability (HRV) was decreased in MI-CHF and AV-CHF vs. Sham condition. (B) MI-CHF and AV-CHF rats display cardiac parasympathetic withdrawal and enhanced sympathetic cardiac tone as evidenced by a decreased tachycardic response (ΔHR) following i.p. bolus of atropine (1 mg/kg) and an increased bradycardic response (C) following propranolol (1 mg/kg, i.p.), respectively. ***p < 0.001, **p < 0.01 and *p < 0.05 vs. Sham condition, Sidak post-hoc test after one-away ANOVA, n = 4 rats.

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  Figure 5. Incidence of apnea-hypopnea in rats with low output heart failure (MI-CHF) and high output heart failure (AV-CHF). The apnea-hypopnea index (AHI) was increased in both MI and AV CHF rats vs. Sham condition. **p < 0.01 and *p < 0.05 vs. Sham condition, Sidak post-hoc test after one-way ANOVA, n = 6 rats.

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  Figure 6. Krüppel-like factor 2 (KLF2) expression is reduced in myocardial infarction (MI-CHF) but normal in arteriovenous fistula (AV-CHF) rats. (A) Fluorescence intensity for KLF2 in the CB from MI-CHF was markedly decreased compared to Sham rats. Notably, AV-CHF rats showed similar KLF2 average fluorescence in the CB compared to Sham rats. (B) Representative immunoblots for KLF2 obtained in one Sham rat, one MI-CHF rat and one AV-CHF rat and summary data showing the changes in the expression levels of KFL2 in MI-CHF and in AV-CHF (p = 0.34, Sham vs. MI-CHF; p = 0.68, Sham vs. AV-CHF; Wilcoxon sum-rank test, n = 4). (C) Proposed model showing the role of blood flow in CB sensitization in low vs high output heart failure. MI-CHF rats display reduced blood flow to the CB that leads to a decreased expression of shear stress-sensitive transcription factors (i.e. KLF2) promoting CB glomus cells hyperactivity and finally ending in an enhanced chemoreflex drive. On the contrary, AV-CHF rats display normal blood flow to the CB with no changes in KLF2 expression and normal CB-mediated chemoreflex drive. Dotted lines: extrapolation of the carotid circulation to the carotid bodies.