Effect of renal sympathetic denervation on ventricular and neural remodeling

Abstract

Background: This study assessed the therapeutic effects of renal sympathetic denervation (RDN) on post-myocardial infarction (MI) ventricular remodeling and sympathetic neural remodeling in dogs. The possible mechanisms and optimal time for treatment are discussed.

Methods: We randomly assigned 30 dogs to five groups: RDN 1 week before MI (RDN1w + MI; n = 6), RDN 1 week after MI (MI1w + RDN; n = 6), RDN 2 weeks after MI (MI2w + RDN; n = 6), control (N; n = 6), and MI (n = 6). A canine model of myocardial infarction was established by interventional occlusion with a gelatin sponge via the femoral artery. Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) levels were measured and echocardiography was performed to assess cardiac function and heart size. All dogs were killed at the end of the experiment and samples of cardiac and renal arteries were obtained. The expression of matrix metalloproteinase (MMP)-2 and MMP-9 in cardiac and of tyrosine hydroxylase (TH) in renal arteries was assessed by immunohistochemistry. Sympathetic innervations in the infarction border zone were investigated via Western blotting and real-time PCR.

Results: Left ventricular function in the MI group decreased significantly, while plasma BNP and ET-1 levels as well as MMP-2 and MMP-9 expression increased. Compared with the MI group, the RD groups showed significantly reduced MMP‑2, MMP‑9, TH, and growth-associated protein (GAP) 43 expression in the RDN1w + MI, MI1w + RDN, and MI2w + RDN groups was significantly improved. Additionally, the expression of TH in renal arteries decreased after RDN.

Conclusion: RDN has preventive and therapeutic effects on post-MI ventricular remodeling and sympathetic neural remodeling. The mechanism of RDN is likely mediated through restraint of renal sympathetic nerve activity.

Keywords: Cardiac remodeling; Experimental animal model; Heart attack; Myocardial infarction; Sympathectomy.

Fig. 1

Level of (a) brain natriuretic peptide (BNP) and of (b) endothelin-1 (ET-1) 4 weeks after myocardial infarction (MI).Data are mean ± SD obtained from baseline and 4 weeks after MI. ^§p < 0.05: group comparison; ^*p < 0.05 vs. N group; ^#p < 0.05 vs. MI group

Fig. 2

Left ventricular ejection fraction (LVEF), interventricular septal thickness (IVSd), left ventricular posterior wall thickness (LVPWd), and left ventricular end-diastolic diameter (LVEDd) measured at baseline, 1 week after MI, and 4 weeks after MI in the five study groups: RDN1w +MI RDN 1 week before MI, MI1w +RDN, RDN 1 week after MI, MI2w +RDN RDN 2 weeks after MI, N control group, MI myocardial infarction group (see text for details)

Fig. 3

a Tyrosine hydroxylase (TH) nerve fiber staining. a non-RDN groups (left): the distribution of TH-positive nerve fibers is thickened and disorderly (arrows); RDN groups (right): TH-positive nerve fibers in renal artery are significantly decreased with orderly distribution (arrow). b Expression of TH-positive nerve fibers in the renal artery. IHS immunohistochemical score. ×400

Fig. 4

a Matrix metalloproteinase (MMP)-2 and b MMP-9 immunohistochemical staining of the infarct border zone. ×400. From left to right: RDN1w + MI group, MI1w + RDN group, MI2w + RDN group, N group, and MI group (see text for details)

Fig. 5

Immunohistochemical score (IHS) for matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expression. Data are mean ± SD obtained 4 weeks after MI. *p < 0.05 vs. N group, #p < 0.05 vs. MI group (see text for details)

Fig. 6

a Western blots and graphs showing protein expression of (a, c) tyrosine hydroxylase (TH) and β-actin as well as of (b, d) GAP43 and β-actin in the peri-infarct zone (c, d mean ± SD). A RDN1w + MI group, B MI1w + RDN group, C MI2w + RDN group, D N group, E MI group

Fig. 7

mRNA levels of nerve growth factor (NGF) quantified in the peri-infarct zone. Data are mean ± SD obtained from baseline and 4 weeks after MI. ^△p < 0.05 vs. MI2w + RDN group, ^*p < 0.05 vs. N group, ^#p < 0.05 vs. MI group (see text for details)