Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure

Abstract

The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.

Keywords: autonomic nervous system; heart failure.

Figure 1

A-C, original tracing (A) and mean data showing the cardiovascular (B) and sympathetic (C) responses to epicardial application of either capsaicin or bradykinin (10μg/ml) in sham+vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats (n=8-12/each group). Scale bar in A represents 30 seconds. D and E, basal cardiac (n=6-8/each group) and renal sympathetic nerve activity (n=8-12/each group) and urinary NE secretion (E, n=6/each group) in sham+vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats. Values are mean ± SE. *P<0.05 vs. sham+vehicle; †, P<0.05 vs. CHF+vehicle.

Figure 2

Representative tracings (A) and mean data (B) showing basal dp/dt_max and diastolic dp/dt_min as well as the dose-dependent responses to beta-adrenergic receptor stimulation with ISO (0.01, 0.1 and 1.0 μg/kg, 0.2 ml). Values are mean ± SE. n=6/each group. *P<0.05 vs. sham+vehicle; †, P<0.05 vs. CHF+vehicle.

Figure 3

A, representative sirus red stain (top) and mean data (bottom right) showing that RTX reduces cardiac fibrosis induced by myocardium infarction (MI); bottom left, Masson’s trichrome staining showing similar infarcted size between CHF+Vehicle and CHF+RTX rats in top panel. Black arrows point to the sirius red-positive staining. B-D, western blotting data showing the protein expression of α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor (TGF) beta 1 and β1-adrenergic receptors (β1-AR) in the left ventricle (remote region) and septum in sham+Vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats. Data are expressed as mean±SE. n=6/each group. *, P<0.05 vs. sham+vehicle, †, P<0.05 vs. CHF+vehicle.

Figure 4

Original tracing (A) and mean data (B) showing baroreflex curves and gain in sham+vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats. Data are expressed as mean±SE. n=8-10/each group. * P<0.05 vs. sham+vehicle and sham+RTX and CHF+RTX.

Figure 5

A-D, original 10-sec recordings of steady state P-V loops obtained with a Millar P-V conductance catheter system from sham+vehicle, sham+RTX, CHF+vehicle and CHF+RTX rats. E and F, mean data showing the effect of RTX on the systolic (ESPVR, E) and diastolic (EDPVR, F) function that are independent of systemic vascular resistance in sham and CHF rats. Data are expressed as mean±SE. n=7-8/each group. *, P<0.05 vs. sham+vehicle, †, P<0.05 vs. CHF+vehicle.

Figure 6

Representative scanning images (A) and mean data (B-D) showing TUNEL-positive staining in LV infarct, LV peri-infarct, LV remote and IVS regions from sham+vehicle, sham+RTX, CHF+Vehicle and CHF+RTX rats. Data are expressed as mean±SE. n=5-6/each group. *, P<0.05 vs. sham+vehicle, †, P<0.05 vs. CHF+vehicle.