Cardiac sympathetic afferent reflex control of cardiac function in normal and chronic heart failure states

Abstract

Key points: Cardiac sympathetic afferents are considered to be essential pathways for transmission of cardiac nociception to the central nervous system during myocardial ischaemia. However, a potential contribution of the CSAR control of cardiac dysfunction in both normal and chronic heart failure (CHF) states remains unknown. We found that activation of the CSAR evokes little increase in cardiac contractility with an exaggerated peripheral vasoconstriction in the CHF state. CSAR inhibition by epicardial lidocaine decreased cardiac contractility to a greater extent in CHF rats than sham rats. Furthermore, we also found that epicardial lidocaine paradoxically decreased left ventricular end-diastolic pressure (LVEDP) and left ventricular end-diastolic volume (preload) in CHF rats, which was not observed in sham rats. Chronic ablation of the CSAR by epicardial application of the afferent neurotoxin, RTX, selectively lowered diastolic blood pressure CHF rats. The observation suggests that CSAR has a differential effect on cardiac function in normal and CHF states. CSAR activation in normal state causes significant increase in cardiac contractility and cardiac output.

Abstract: The enhanced 'cardiac sympathetic afferent reflex' (CSAR) critically contributes to the exaggerated global sympathetic tone in chronic heart failure (CHF). However, a potential contribution of the cardio-cardiac reflex control of cardiac function in both normal and CHF states remains unknown. In this study, we evaluated the effects of direct activation or inhibition of the CSAR on cardiac function by pressure-volume (P-V) loop analysis in ∼12-week sham-operated and myocardial infarcted (MI) rats. In sham rats, acute CSAR activation by epicardial application of bradykinin (BK) increased heart rate (HR), left ventricular systolic pressure (LVSP), the maximum first derivative of left ventricular pressure (dp/dt_max ), and the slope of the end-systolic P-V relationship (ESPVR), suggesting that acute CSAR activation in the normal state enhances myocardial contractility. CSAR activation also decreased left ventricular (LV) systolic and diastolic volumes with little effect on LV end-diastolic pressure (LVEDP) or the end-diastolic P-V relationship (EDPVR) in sham rats. Compared to sham, CHF rats exhibit a reduced increase in the slope of the ESPVR and dp/dt_max in response to BK, indicating a poor contractile response to CSAR activation. Interestingly, BK application in CHF rats increased cardiac systolic and diastolic volumes and further increased the elevated LVEDP, neither of which was seen in sham rats. Following CSAR inhibition by epicardial lidocaine, blood pressure, HR, LVSP, dp/dt, LVEDP and ESPVR decreased in CHF rats whereas lidocaine had little effect in sham rats, indicating that the CSAR is tonically active in CHF and contributes to cardiac dysfunction. Furthermore, we found that epicardial lidocaine paradoxically decreased LV end-diastolic volume (preload) in CHF rats, which was not observed in sham rats. The decreased preload by lidocaine in CHF rats may be due to a reduction in peripheral vascular resistance since epicardial lidocaine significantly lowered peripheral (renal) sympathetic nerve activity in CHF rats but not in sham rats. Furthermore, chronic ablation of CSAR by epicardial application of a selective afferent neurotoxin, resiniferatoxin, selectively lowered diastolic blood pressure both at daytime and night-time with less effect on systolic blood pressure in CHF rats. Our data suggest that there is an imbalance between cardiac and peripheral responses to CSAR in CHF animals compared to sham-operated controls.

Keywords: autonomic dysfunction; cardiac dysfunction; cardiovascular reflexes; sympathetic nerve activity.

Figure 1. Representative tracings showing cardiac functional changes in response to epicardial application of bradykinin (BK, 10 μg ml⁻¹) in a sham (A) or CHF (B) rat

a–d, 2 s recordings before and after BK from A and B as shown. Note that LVEDP was dramatically increased in the CHF rat after epicardial application of BK whereas it was not affected by BK in the sham rat.

Figure 2. Representative tracings and summary data showing that there were differential changes in systolic (end‐systolic pressure–volume relationship, ESPVR) function and left ventricle end‐diastolic pressure (LVEDP) in responses to epicardial application of bradykinin (BK, 10 μg ml⁻¹) or 2% lidocaine (Lido) in sham and CHF rats

A and B, original recordings of steady state P–V loops obtained with a Millar P–V conductance catheter system before and after epicardial application of BK in sham and CHF rats. Red line represents ESPVR and the blue curved line demonstrates the diastolic (end‐diastolic pressure–volume relationship, EDPVR) function, both of which are independent of systemic vascular resistance. C, individual (black and white symbols) and average (red symbols) data showing changes in ESPVR in response to epicardial application of either BK or lido in sham and CHF rats. D, individual (black and white symbols) and average (red symbols) data showing changes in LVEDP in response to epicardial application of either BK or lido in sham and CHF rats. Data are expressed as means ± SEM. ^* P < 0.05 vs. sham rats. NS, not significant.

Figure 3. Representative tracing showing cardiac functional changes in response to epicardial application of 2% lidocaine in a sham (A) or CHF (B) rat

a–d, 2 s recordings before and after lidocaine from A and B as shown. Note that LVEDP was dramatically decreased in the CHF rat after epicardial application of lidocaine whereas it was less affected by lidocaine in the sham rat.

Figure 4. Representative tracings (A) and summary data (B and C) showing that acute epicardial application of either bradykinin (BK) or 2% lidocaine increased or decreased, respectively, mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) to a greater extent in the CHF rats compared to sham rats (n = 8 in each group)

Data are expressed as means ± SEM. ^* P < 0.05 vs. sham.

Figure 5. Conscious 24‐h telemetry blood pressure data showing the effects of chronic cardiac sympathetic afferent denervation by epicardial application of RTX (50 μg ml⁻¹) on mean arterial pressure (MAP, A), heart rate (HR, B), systolic blood pressure (SBP, C) and diastolic blood pressure (DBP, D) in CHF rats 12 weeks post‐MI

Sham rats served as controls. Data are expressed as means ± SEM. n = 6–7 in each group. ^* P < 0.05 vs. CHF + vehicle.

Figure 6. Conscious daytime (A) and night‐time (B) telemetry blood pressure data showing the effects of chronic cardiac sympathetic afferent denervation by epicardial application of RTX (50 μg ml⁻¹) on mean arterial pressure (MAP), heart rate (HR), systolic arterial pressure (SBP) and diastolic blood pressure (DBP) in CHF rats 12 weeks post‐myocardial infarction

Data are expressed as means ± SEM. n = 6–7 in each group. ^* P < 0.05 vs. sham. †P < 0.05 vs. CHF + vehicle.

Figure 7. A schematic diagram describing how CSAR regulates cardiac function in the normal and CHF states

Activation of the CSAR causes a potent increase in cardiac contractility with a moderate increase in peripheral vasoconstriction in the normal state, which results in increased cardiac output with decreased cardiac diastolic and systolic volumes. However, activation of the CSAR causes very little increase in cardiac contractility with an exaggerated peripheral vasoconstriction in the CHF state, which causes a small increase in cardiac output associated with increased cardiac systolic and diastolic volumes and LVEDP.