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      Renal Denervation Therapy for the Treatment of Arrhythmias: Is the Sky the Limit?

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          Abstract

          Introduction As the life expectancy of the general population continues to increase, cardiovascular disease is becoming an increasingly important driver of morbidity and mortality. Many of the recent advancements in our treatment armamentarium against cardiovascular disease center around curbing maladaptive responses to stress. Specifically, neurohormonal modulatory medications are the cornerstones of therapy in patients who suffer myocardial infarction and/or develop systolic heart failure. In such patients compensatory mechanisms become drivers of cardiac pathology.1 Autonomic dysregulation leads to excessive sympathetic drive, which in turn causes blunted natriuresis and hypertension.2 Medications such as β‐blockers, ACE inhibitors, and aldosterone inhibitors3, 4, 5, 6 help to mitigate adverse neurohormonal changes and improve outcomes in patients with heart failure. Furthermore, medications that interrupt the renin‐angiotensin‐aldosterone system have been shown to have antifibrotic properties in animal models, as they appear to reduce cardiac fibroblast proliferation and collagen deposition.7 Optimizing a medication regimen remains the cornerstone of heart failure therapy, but new invasive catheter‐based techniques are being developed and investigated as disease‐modifying tools in heart failure. As an example, catheter‐based renal denervation (RDN) was conceived as a rational therapy for patients with resistant hypertension.8, 9 Subsequently, this technology was brought to bear on other types of patients in whom modulation of cardiorenal interplay was hypothesized to be beneficial. Of late, there has been increasing interest in using RDN for the treatment and prevention of arrhythmias and arrhythmia‐related morbidity. Animal studies have shown promise. In a canine model of tachycardia‐mediated cardiomyopathy, RDN was shown to attenuate ventricular remodeling in animals that are chronically paced at a high rate.10 In a pig model of myocardial infarction, investigators subjected the animals to myocardial ischemia using 20 minutes of LAD occlusion. Half of the pigs had had RDN, and half underwent a sham procedure. RDN significantly decreased occurrence of ventricular fibrillation during occlusion.11 There is a paucity of detailed human research on the subject, but some small studies have suggested that RDN could be an effective adjunct to catheter ablation for atrial fibrillation (AF). Pokushalov and colleagues randomized 27 patients with refractory AF and resistant hypertension to pulmonary vein isolation alone vs pulmonary vein isolation plus catheter‐based RDN; they found significantly improved arrhythmia control in the RDN arm at 1‐year of follow‐up.12 Two articles published in this issue of JAHA explore the pathophysiologic role of renal nerve activity in cardiovascular disease progression in animal models, with a focus on arrhythmia. They serve as forward steps toward expanding the indication for RDN to be used as adjunct therapy for the suppression of AF and the prevention/treatment of premature ventricular contraction (PVC)–mediated cardiomyopathy. These articles approach the issue from opposite angles. Yamada and colleagues examine whether RDN can prevent PVC‐mediated cardiomyopathy.13 Yu and colleagues attempt to deconstruct the observations from prior animal and human studies that RDN could decrease the incidence of AF; they examine the mechanisms by which renal sympathetic nerve stimulation affects the threshold for the induction of atrial fibrillation.14 Yamada et al studied 18 rabbits—6 controls, 6 with a 50% PVC burden, and 6 with a 50% PVC burden plus RDN. The PVCs were generated through epicardial left ventricular apical pacing; RDN surgery involved cutting of visible nerves at the renal hilus (bilaterally) along with adventitial stripping of the renal artery. The controls had sham procedures performed for pacing and RDN. The animals were followed for 5 weeks, at which point they underwent echocardiography, electrophysiology study, and pathologic analysis of harvested myocardium. Yamada et al found that the rabbits with high PVC burden without RDN developed left ventricular enlargement and biventricular fibrosis. Additionally, these animals were more readily induced into ventricular fibrillation during programmed ventricular stimulation. Importantly, the animals with PVCs plus RDN fared comparably to the controls.13 Yu et al studied 28 dogs and sutured electrode catheters to their renal arteries. They then performed 3 hours of high‐frequency stimulation at the proximal, mid, and distal portions of the renal artery. With renal nerve stimulation, they observed a hypertensive response, shortening of the effective refractory period at a number of atrial sites, and a widening of the window of vulnerability for AF induction. Importantly, the authors demonstrate that the proximal portion of the renal artery appears to be the most important in cardiorenal interplay; stimulation at this proximal portion of the renal artery produced the greatest hemodynamic effect and the most pronounced shortening of atrial refractory periods. C‐fos and NGF gene and protein expression as well as left stellate ganglion activity and superior left ganglionic plexus activity were also measured in response to renal nerve stimulation. The authors note upregulation and increased activity of all of the above and make the claim that left stellate ganglion and superior left ganglionic plexus activation is the mechanism by which renal nerve stimulation “exerts pro‐fibrillatory effects on the atrium.”14 This conclusion is not well substantiated, as no causative relationship can be drawn from the data provided. Ultimately, the authors are left describing phenomenology and not a true biochemical blueprint for how renal nerve stimulation modulates atrial electrophysiologic properties. The studies by Yamada and Yu represent small but important incremental steps in defining the role of renal afferents in modulating the cardiac electrical milieu and in serving as a key link in the pathologic cardiac response to hemodynamic stress. The documented effects of renal nerve activation/inhibition on both arrhythmogenesis and ventricular dysfunction speak to the close link between kidney and heart. Although these studies are intriguing, they are clearly only hypothesis generating, as they employ animal models, small sample sizes, and limited monitoring time frames. The mechanisms by which renal nerve manipulations affect arrhythmogenesis are, as yet, incompletely elucidated. Future directions for investigation should include follow‐up animal studies first—for instance, it would be of great interest to allow subjects to develop a PVC‐mediated cardiomyopathy prior to performing RDN; an examination of whether RDN is capable of fostering reverse ventricular remodeling would be informative for the practical scope of this modality. Likewise, a before‐and‐after RDN study of AF inducibility would be useful because allowing each animal to be its own control may allow for more credible conclusions. Eventually, it is conceivable that RDN could be used in humans both to prevent arrhythmia (atrial and ventricular) and also to treat the adverse sequelae of arrhythmia (ie, tachycardia‐mediated cardiomyopathy in AF, heart failure with preserved ejection fraction in AF, and PVC‐mediated cardiomyopathy). Clinical scenarios in which RDN might be used are myriad; these include the prevention/treatment of cardiomyopathies associated with PVCs that are not suppressed with antiarrhythmic drugs and not amenable to catheter ablation, as a same‐procedure adjunct to AF ablation, and as a treatment for ventricular storm and other ventricular tachyarrhythmias refractory to conventional therapies. Renal denervation might also be useful for niche indications such as a less invasive alternative to thoracoscopic sympathectomy in patients with long‐QT syndrome. As with all new invasive interventions, careful patient selection and refining and standardization of procedural techniques are paramount. When considering new invasive therapeutic interventions, it is important to be mindful of the potential damage that can result. Catheter‐based approaches for RDN are inherently associated with a risk of vascular complications.15 As always, the unintended consequences of manipulating the body's adaptive mechanisms may not become clear until a given therapy is applied in a substantial number of people (with long periods of follow‐up). Last, any future trials of RDN therapy must be designed with robust sham procedure arms. As was shown by the SYMPLICITY HTN3 investigators, the influence of a sham placebo is powerful—in examining the blood pressure benefit of bilateral catheter‐based RDN, they found (to everyone's surprise) no significant antihypertensive effect of RDN.16, 17 With the above caveats in mind, the future looks bright for the use of RDN in arrhythmia control. Disclosures None.

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          A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension.

          The aim of this prospective randomized study was to assess the impact of renal artery denervation in patients with a history of refractory atrial fibrillation (AF) and drug-resistant hypertension who were referred for pulmonary vein isolation (PVI). Hypertension is the most common cardiovascular condition responsible for the development and maintenance of AF. Treating drug-resistant hypertension with renal denervation has been reported to control blood pressure, but any effect on AF is unknown. Patients with a history of symptomatic paroxysmal or persistent AF refractory to ≥2 antiarrhythmic drugs and drug-resistant hypertension (systolic blood pressure >160 mm Hg despite triple drug therapy) were eligible for enrolment. Consenting patients were randomized to PVI only or PVI with renal artery denervation. All patients were followed ≥1 year to assess maintenance of sinus rhythm and to monitor changes in blood pressure. Twenty-seven patients were enrolled, and 14 were randomized to PVI only, and 13 were randomized to PVI with renal artery denervation. At the end of the follow-up, significant reductions in systolic (from 181 ± 7 to 156 ± 5, p < 0.001) and diastolic blood pressure (from 97 ± 6 to 87 ± 4, p < 0.001) were observed in patients treated with PVI with renal denervation without significant change in the PVI only group. Nine of the 13 patients (69%) treated with PVI with renal denervation were AF-free at the 12-month post-ablation follow-up examination versus 4 (29%) of the 14 patients in the PVI-only group (p = 0.033). Renal artery denervation reduces systolic and diastolic blood pressure in patients with drug-resistant hypertension and reduces AF recurrences when combined with PVI. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs.

            Increased sympathetic activation during acute ventricular ischemia is involved in the occurrence of life-threatening arrhythmias. To test the effect of sympathetic inhibition by renal denervation (RDN) on ventricular ischemia/reperfusion arrhythmias. Anesthetized pigs, randomized to RDN or SHAM treatment, were subjected to 20 minutes of left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size, hemodynamics, premature ventricular contractions, and spontaneous ventricular tachyarrhythmias were analyzed. Monophasic action potentials were recorded with an epicardial probe at the ischemic area. Ventricular ischemia resulted in an acute reduction of blood pressure (-29%) and peak left ventricular pressure rise (-40%), which were not significantly affected by RDN. However, elevation of left ventricular end-diastolic pressure (LVEDP) during LAD ligation was attenuated by RDN (ΔLVEDP: +1.8 ± 0.6 mm Hg vs +9.7 ± 1 mm Hg in the SHAM group; P = .046). Infarct size was not affected by RDN compared to SHAM. RDN significantly reduced spontaneous ventricular extrabeats (160 ± 15/10 min in the RDN group vs 422 ± 36/10 min in the SHAM group; P = .021) without affecting coupling intervals. In 5 of 6 SHAM-treated animals, ventricular fibrillation (VF) occurred during LAD occlusion. By contrast, only 1 of 7 RDN-treated animals experienced VF (P = .029). Beta-receptor blockade by atenolol showed comparable effects. Neither VF nor transient shortening of monophasic action potential duration during reperfusion was inhibited by RDN. RDN reduced the occurrence of ventricular arrhythmias/fibrillation and attenuated the rise in LVEDP during left ventricular ischemia without affecting infarct size, changes in ventricular contractility, blood pressure, and reperfusion arrhythmias. Therefore, RDN may protect from ventricular arrhythmias during ischemic events. © 2013 Heart Rhythm Society. All rights reserved.
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              Neurohumoral stimulation.

              The temporal relationship between the development of heart failure and activation of the neurohumoral systems involved in chronic heart failure (CHF) has not been precisely defined. When a compensatory mechanism switches to a deleterious contributing factor in the progression of the disease is unclear. This article addresses these issues through evaluating the contribution of various cardiovascular reflexes and cellular mechanisms to the sympathoexcitation in CHF. It also sheds light on some of the important central mechanisms that contribute to the increase in sympathetic nerve activity in CHF. 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                pdbhave@gmail.com
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                02 March 2017
                March 2017
                : 6
                : 3 ( doiID: 10.1002/jah3.2017.6.issue-3 )
                : e005342
                Affiliations
                [ 1 ] Divison of Cardiology Wake Forest University Health Sciences Center Winston‐Salem NC
                Author notes
                [*] [* ] Correspondence to: Prashant D. Bhave, MD, FHRS, Cardiology Division/Electrophysiology Section, Wake Forest Baptist Hospital, 1 Medical Center Blvd, Winston‐Salem, NC 27157. E‐mail: pdbhave@ 123456gmail.com
                Article
                JAH32129
                10.1161/JAHA.116.005342
                5524038
                28255080
                2d939617-960d-4a7d-8d2e-0defd6520741
                © 2017 The Author. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Page count
                Figures: 0, Tables: 0, Pages: 3, Words: 1992
                Categories
                Editorial
                Editorial
                Custom metadata
                2.0
                jah32129
                March 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.3 mode:remove_FC converted:11.07.2017

                Cardiovascular Medicine
                editorials,arrhythmia,autonomic nervous system,remodeling heart failure,renin angiotensin system,arrhythmias

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