Chronic Kidney Disease: A Nerve-Racking Situation for the Heart.

Abstract

HomeCirculation ResearchVol. 130, No. 6Chronic Kidney Disease: A Nerve-Racking Situation for the Heart Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBChronic Kidney Disease: A Nerve-Racking Situation for the Heart Olujimi A. Ajijola Olujimi A. AjijolaOlujimi A. Ajijola Correspondence to: Olujimi A. Ajijola, MD, PhD, UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, CA 90095. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6197-7593 UCLA Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence. David Geffen School of Medicine at UCLA, Los Angeles, CA. Search for more papers by this author Originally published25 Feb 2022https://doi.org/10.1161/CIRCRESAHA.122.320858Circulation Research. 2022;130:829–830This article is a commentary on the followingRenal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKDOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 25, 2022: Ahead of Print Article, see p 814Atrial fibrillation (AF) remains the most common sustained arrhythmia in adults.1 Despite much effort, it places a significant burden on health care costs and is difficult to manage. The challenges in management are related to incomplete understanding its pathophysiology. Consequently, the introduction of novel therapeutic approaches against AF has been slow, compared with stroke risk reduction using novel oral anticoagulants. Catheter ablation offers significantly better rhythm control as compared with pharmacological agents but is plagued by unacceptably high recurrence rates, particularly in patients with persistent AF. With an aging US population, calling the need for novel AF therapies urgent is an understatement.In this issue of the journal, Hohl et al2 explore the link between chronic kidney disease (CKD) and AF. Specifically, the authors examined whether sympathetic remodeling induced by CKD mediates structural and functional remodeling of the atria, increasing susceptibility to AF. The authors investigated this link in an Adenine model of CKD, randomizing rats with CKD to renal denervation (RDN) or a sham procedure. To confirm effective RDN, the authors demonstrated reduced renal norepinephrine content and tyrosine hydroxylase protein expression, as well as reduced immunostaining for tyrosine hydroxylase. Following RDN, rats with CKD exhibited reduced left ventricular wall thickness and improved diastolic function.In the left atrium, RDN improved geometric, structural, and electrophysiology remodeling induced by CKD. Specifically, left atrium diameter and area were smaller in CKD+RDN versus CKD animals. In addition, interstitial fibrosis and sympathetic hyperinnervation in left atrium caused by CKD were attenuated by RDN, as was TH protein expression determined by Western blotting. Importantly, these markers of structural and autonomic remodeling in CKD animals were associated with electrophysiological alterations. Electrocardiographic P-wave duration, as well as the inducibility and duration of AF, which were increased in CKD animals compared with controls, were attenuated by RDN. Electrical mapping studies implicated conduction latency (ie, slowed conduction velocity) and activation heterogeneity as mechanisms through which RDN exerted protective effects on the atria.These studies demonstrated that renal dysfunction is associated with left atrial hyperinnervation, fibrosis, and arrhythmogenesis, which are attenuated by RDN. While it does not indicate causality, it supports the implication of CKD in the pathogenesis of AF, and directly suggests that effective RDN may benefit patients with CKD with or at risk for AF. Of note, there is emerging evidence that neuromodulation is likely to have an increasingly important role in the management of AF.3The authors are to be commended for their detailed study establishing the association between RDN and protection from atrial remodeling and atrial arrhythmogenesis. It builds on the ERADICATE-AF (Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension) study,4 a single-blind randomized clinical trial that demonstrated improved freedom from atrial arrhythmias at 12 months when RDN was added to catheter ablation of AF. Interestingly, the addition of RDN to bilateral cardiac sympathetic denervation also demonstrated efficacy in patients with recalcitrant ventricular tachycardia or fibrillation (VT/VF).5 Further, in a large animal model of ischemia-induced VT/VF,6 aortico-renal ganglion ablation reduced the risk of VT/VF compared with sham ablation pigs. These latter studies suggest that the benefits of RDN extend to both atrial and ventricular arrhythmias.There are several implications of the study to consider. First, it emphasizes, yet again, the need to overcome the challenges associated with RDN in a clinical setting.7 While promising initial studies led to the initiation of large randomized clinical trials of catheter-based renal artery denervation, the results of those trials were disappointing. Myriad factors are associated with limited consistent efficacy across patients undergoing RDN including reinnervation, anatomic variability, renal arterial vasculature acting as heat sinks, lack of established end points, and others. Yet, preclinical studies demonstrate efficacy against a variety of chronic diseases when RDN is effective. Studies such as that by Hohl and colleagues continue to make the case for improved strategies that effectively denervate the kidneys. It is likely that if effective RDN can be consistently achieved in most or all patients attempted, it would enable a significant reduction in the burden and pathogenesis of several cardiovascular diseases. The call for therapies that effectively denervate, or better yet, adequately target renal afferent neurotransmission, could not be louder.In terms of mechanism, sympathetic overactivity is an established finding in CKD. Similarly, in chronic cardiac injury such as chronic myocardial infarction or chronic heart failure, sympathetic overactivity is also a hallmark. Afferent neurotransmission from the kidneys and heart are implicated in sympathoexcitation in CKD and myocardial infarction/chronic heart failure, respectively. Selective targeting of cardiac afferents improve cardiac remodeling and reduce renal sympathetic nerve activity.8,9 The data in the present study suggest that targeting renal innervation similarly attenuates sympathetic overactivity to the heart. Similar relationships have been identified between the heart and lung, where chronic lung injury is associated with sympathetic dysfunction and ventricular arrhythmias.10 Evidence continues to accumulate to suggest that autonomic neuromodulation may be a logical target to attenuate the risk of multiorgan dysfunction arising from chronic injury to one organ. This concept is interesting, novel, and timely, and is emphasized by the interest of the National Heart Lung and Blood Institute in identifying research opportunities that further our understanding of cardiopulmonary diseases.11In conclusion, the study by Hohl, Selejan, Wintrich, and their colleagues supports the notion that chronic sympathetic overactivity in CKD promotes dysfunction in other organs, and provides a novel dimension in considering pathophysiology of multiorgan dysfunction. Notably kidney disease also represents a state where uremic toxins are likely to increase the proclivity to adverse electrophysiological effects on cardiac myocytes12; however, the current study explores a novel angle and implicates sympathetic hyperactivity. The work also highlights the need for continued investigations based on the principles of integrative physiology in health and disease. Importantly, it strongly suggests that RDN as a therapeutic strategy for hypertension and other chronic cardiovascular diseases, is worthy of further study, and the scientific rationale for the work is strengthened by this study. Finally, it continues the resounding call for effective RDN strategies from which patients will undoubtedly benefit.Article InformationSources of FundingDr Ajijola is supported by NIH DP2OD024323, HL159001, and OT2 OD023848.DisclosuresDr Ajijola reports being a co-founder of NeuCures, Inc. The Regents of UCLA own intellectual property relevant to cardiac neuromodulation.FootnotesFor Sources of Funding and Disclosures, see page 830.Correspondence to: Olujimi A. Ajijola, MD, PhD, UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, CA 90095. Email [email protected]ucla.edu