Effects of renal denervation on the development of post-myocardial infarction heart failure and cardiac autonomic nervous system in rats

Abstract

Prior studies indicated that radiofrequency renal denervation (RD)had beneficial effects on post-myocardial infarction (MI) heart failure(HF) in rats[1–3]. In this studywe aimedtoassessits effects on cardiacautonomic nervous system (CANS) which might be one of the mostimportant mechanisms of RD's therapeutic effect on post-MI HF anddetermine the best timing for RD.One hundred Wistar rats were randomly assigned intofiveexperimental groups: MI group (n = 20), RD group (n = 20),MI-1d + RD group (RD performed one day post-MI, n = 20),MI-4w + RD group (RD performed four weeks post-MI, n = 20),andNgroup(controlgroup, n = 20).MIwasproducedthroughligationof the anterior descending artery. RD was performed through strippingof the renal nerves. The experimental design and implementation wereconducted in accordance with animal welfare guidelines.Eight weeks post-MI, significant improvements were observed inboth MI-1d + RD and MI-4w + RD groups compared to the MIgroup, that include (1) improved left ventricular (LV) function andhemodynamics with increased water and sodium excretion;(2) decreased plasma and renal tissue norepinephrine levelswhile tissue norepinephrine content increased in myocardium;(3) increased β1-receptor in myocardium and improved heartratevariability;and(4)decreasedplasmarenin,angiotensinII,aldoste-rone,BNPandendothelinlevels.Moretherapeuticeffectswerefoundinthe MI-1d + RD group than the MI-4w + RD group (see Table 1 andFig. 1).Firstly, our study showed that RD attenuated the remodeling ofCANS and modulated its activities. RD leads to preservation of β1receptors content along with the β1 mRNA expression in non-infarcted cardiac tissue in this HF model (Fig. 1). This correlated withan improvement in heart function and cardiac remodeling. HRV is asensitive marker for the CANS [4]. RD led to a slower HR and higherSDNN in both intervention groups (See Table 1). The increase in SDNNindicates that cardiac sympathetic over-activation was suppressed andvagal activity was enhanced with the result of stabilizing cardiacelectrical activity, decreasing malignant arrhythmias, thereby reducingthe incidence of sudden death.Secondly, we found that RD blocked both peripheral and centralRAAS and sympathetic nervous system (SNS) at the same time. Andthis may answer the question how RD exerted effect on CANS. In ourstudy RD restores renin, angiotensin II, and aldosterone to near-normal levels. This not only explains the increase in sodium and waterexcretion, but also confirms that RD blocks renal RAAS via blockage ofthe efferent renal sympathetic nerves which is consistent with ourprevious study [2]. Studies have shown that angiotensin II not onlyactivates the central and peripheral SNS, function as part of a positivefeedback cycle between RAAS and the SNS, but also activates the localRAAS of other organs, notably the heart [5]. Our study also showedthat the plasma NE level in MI-1d + RD and MI-4w + RD groupsdecreased significantly, which reflects an overall reduction ofsympathetic activity, and especially represents reduction of centralsympathetic activity. This result maybe in part due to blockade of therenal sympathetic afferent pathway by RD. Furthermore, previousstudies have shown that during HF, the tissue NE levels of both theheart and kidney are decreased due to depletion, decreased reuptakeand increased spillover. The decrease of the tissue NE level causedfeedback activation of the central sympathetic system [6].Thus,increased tissue NE level may alleviate the activation of the centralsympathetic system, which was reflected by our data (Fig. 1).Many studies have shown that central RAAS stimulates the central