Autonomic modulation for the management of patients with chronic heart failure.

Abstract

HomeCirculation: Heart FailureVol. 8, No. 3Autonomic Modulation for the Management of Patients with Chronic Heart Failure Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBAutonomic Modulation for the Management of Patients with Chronic Heart Failure Peter J. Schwartz, MD, Maria Teresa La Rovere, MD, Gaetano M. De Ferrari, MD and Douglas L. Mann, MD Peter J. SchwartzPeter J. Schwartz From the Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (P.J.S.); Department of Cardiology, Fondazione “Salvatore Maugeri”, IRCCS Istituto Scientifico di Montescano, Montescano, Pavia, Italy (M.T.L.R.); Department of Cardiology and Cardiovascular Clinical Research Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.M.D.F.); and Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO (D.L.M.). Search for more papers by this author , Maria Teresa La RovereMaria Teresa La Rovere From the Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (P.J.S.); Department of Cardiology, Fondazione “Salvatore Maugeri”, IRCCS Istituto Scientifico di Montescano, Montescano, Pavia, Italy (M.T.L.R.); Department of Cardiology and Cardiovascular Clinical Research Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.M.D.F.); and Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO (D.L.M.). Search for more papers by this author , Gaetano M. De FerrariGaetano M. De Ferrari From the Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (P.J.S.); Department of Cardiology, Fondazione “Salvatore Maugeri”, IRCCS Istituto Scientifico di Montescano, Montescano, Pavia, Italy (M.T.L.R.); Department of Cardiology and Cardiovascular Clinical Research Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.M.D.F.); and Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO (D.L.M.). Search for more papers by this author and Douglas L. MannDouglas L. Mann From the Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy (P.J.S.); Department of Cardiology, Fondazione “Salvatore Maugeri”, IRCCS Istituto Scientifico di Montescano, Montescano, Pavia, Italy (M.T.L.R.); Department of Cardiology and Cardiovascular Clinical Research Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.M.D.F.); and Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO (D.L.M.). Search for more papers by this author Originally published1 May 2015https://doi.org/10.1161/CIRCHEARTFAILURE.114.001964Circulation: Heart Failure. 2015;8:619–628Dysregulation of the autonomic nervous system in heart failure (HF) has received considerable attention during the past 3 decades, largely because of the well-recognized association between increased sympathetic activity and the elaboration of biologically active molecules, collectively referred to as neurohormones, that help to maintain cardiovascular homeostasis through increased volume expansion, peripheral arterial vasoconstriction, and increased myocardial contractility. However, high and sustained levels of these biologically active molecules (eg, norepinephrine, angiotensin II, aldosterone) are overtly toxic to the heart and circulation.1 These and other insights have led to the clinical use of neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and β-blockers to treat patients with HF with a reduced left ventricular ejection fraction (LVEF).1 The effectiveness of these pharmacological agents is predominantly because of their ability to directly antagonize the deleterious effects of excessive sympathetic and renin–angiotensin activation. However, the current guideline-directed medical therapy (GDMT) in patients with HF fails to completely restore normal autonomic balance disrupted as a part of HF pathophysiology.During the last decade, a novel approach has generated widespread interest: modulation of the autonomic nervous system as a result of either a one-time intervention (eg, denervation) or of ongoing active therapy (eg, electric stimulation) as a means of further diminishing the sympathovagal imbalance that develops in HF.2,3 Of note, therapeutic neuromodulation with device-based therapies, either with spinal cord stimulation (SCS) or vagal stimulation (VS), has been used safely in patients with chronic pain, epilepsy, and depression, since the 1980s. As noted above, HF with a reduced LVEF is associated with sustained activation of the sympathetic nervous system that is accompanied by a withdrawal of parasympathetic tone. Impaired arterial baroreflexes have been proposed as an important mechanism that contributes to the sympathovagal imbalance present in HF4,5 (Figure 1). Blunting of the peripheral arterial and cardiopulmonary baroreceptors leads to a net increase in efferent sympathetic nerve activity that is accompanied by decreased efferent parasympathetic tone. Accordingly, interest has developed not only toward the reduction of sympathetic activity but also toward the possibility of augmenting vagal tone and reflexes.6Download figureDownload PowerPointFigure 1. Kaplan–Meier survival curves according to dichotomized baroreflex sensitivity (BRS) in patients with heart failure (A) taking and (B) not taking β-blockers, with LVEF of 30% and 26%, respectively. Reprinted from La Rovere et al4 with permission of the publisher. Copyright © 2009 American College of Cardiology Foundation. Published by Elsevier Inc.The first clinical report demonstrating the feasibility of performing chronic stimulation of the vagus in patients with severe HF7 and its continuation in the first multicenter clinical trial7,8 have paved the way for a series of clinical approaches having in common the acceptance of the concept9 that deleterious autonomic imbalance is an appropriate target for treatment and that device-based autonomic modulation by simultaneously decreasing sympathetic and increasing parasympathetic activity may improve outcomes. Such a goal would not be possible with the current pharmacological approaches to HF.Here, we review the experimental basis, rationale, design of ongoing clinical trials that are focused on autonomic modulation in HF, including VS, SCS, renal denervation, baroreceptor activation, and left cardiac sympathetic denervation (LCSD).Vagal StimulationChronic VS is already used clinically for the management of drug-refractory epilepsy10 and, more recently, depression.11 The potential salutary role of VS in the heart was first highlighted by a series of experimental studies culminating in the demonstration that VS prevented ventricular fibrillation induced by acute myocardial ischemia in the setting of a healed myocardial infarction.12,13 In animal models of HF, VS increased survival,14 improved ventricular function,14–16 and has shown anti-inflammatory effects.16 Indeed, the anti-inflammatory effects of VS after ischemia and reperfusion injury are accompanied by a reduction in the number of macrophages and apoptotic cells that is paralleled by decreased levels of circulating proinflammatory cytokines.17 These data point to the likely clinical relevance of the so-called cholinergic anti-inflammatory reflex proposed by Tracey.18In the clinical setting, VS is accomplished by placing an electrode cuff around the right or left cervical vagus, thereby stimulating both the vagal efferent and afferent fibers.7,8 Experimentally, and importantly, stimulation of vagal afferent nerve fibers can have profound effects on the activity of the contralateral vagal efferent (increased activity) and bilaterally of cardiac sympathetic efferent nerve fibers (inhibition of activity), as shown in Figure 2.19Download figureDownload PowerPointFigure 2. Effects of electric stimulation on the neural discharge of a single efferent cardiac vagal fiber in an anesthetized cat. A, Spontaneous activity, (B) electric stimulation (5 V,1.5 ms, 30 Hz) of the cut central end of the left cervical vagus, and (C) electric stimulation (10 V, 1.5 ms, 30 Hz) of the cut central end of the left inferior cardiac nerve. Effects of electric stimulation on the discharge of a single efferent cardiac sympathetic fiber in an intact, anesthetized cat. D, Electric stimulation (6 V,1.5 ms, 30 Hz) of the cut central end of the left vagus and (E) electric stimulation (10 V, 1.5ms, 30 Hz) of the cut central end of the inferior cardiac nerve. The tracings in each section are from top to bottom: respiration (positive-pressure inflation is an upward deflection), systemic arterial blood pressure, ECG, and neural activity. Reprinted from Schwartz et al19 with permission of the publisher. Copyright © 1973, Wolters Kluwer Health.To date, 3 clinical studies of VS have been completed and published20–22 (Table 1). The first-in-man single center study of VS involved 8 patients7 and used the CardioFit 5000 device (BioControl Medical Ltd, Yehud, Israel), which is a closed-loop system comprised of a proprietary bipolar electrode that is surgically implanted around the right vagal nerve, and a right ventricular sensing lead that allows for VS to be synchronized so that the vagal nerve is stimulated after the QRS complex. This study was subsequently extended to a multicenter single-arm open-label phase II study that was designed to assess the safety and tolerability of chronic VS.8 The first pilot study enrolled 32 patients in total (94% men; mean age, 56±11 years) with a history of chronic New York Heart Association (NYHA) class II to IV HF and a LVEF of 23±8%. The patients were already receiving GDMT, including β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and loop diuretics; 19 patients had an implantable cardioverter defibrillator. The stimulation intensity of VS, which was limited by patient symptoms of hoarseness or referred jaw pain, was progressively uptitrated to 4.1±1.2 mA (with 1–2 pulses per cardiac cycle). The resting heart rate decreased significantly during the study from 82±13 to 76±13 beats per minute. At 6 months, 59% of patients improved by at least 1 NYHA class and the Minnesota Living with Heart Failure (MLwHF) Questionnaire quality of life score improved from 49±17 to 32±19, as did the distance on the 6-minute walk test. Blinded 2-dimensional echocardiogram analyses disclosed a significant reduction in LV end-systolic volume and a significant increase in LVEF (from 22±7% to 29±8%), but a nonsignificant decrease in LV end-diastolic volume. A prespecified follow-up of a group of patients at 1 (n=23) and 2 years (n=19) showed that many of the beneficial effects of VS were maintained (Figure 3).Table 1. Characteristics of 3 Just Completed or Ongoing Trials With Vagal Stimulation in Patients With HFStudy NamePhasePatients, nNYHALVEFQRSStimulation SideControl GroupEnd-PointANTHEM-HF20I to II60II–III≤40%, LVEDD≥50 mm and <80 mm≤150R vs LR vs LLVESV; LVESD; LVEFNECTAR-HF21II96II–III≤35%, LVEDD>55 mm<130RStimulation offLVESDINOVATE-HF22III650III≤40%, LVEDD 50–80 mmNARGDMTDeath+HF hospitalizationANTHEM-HF indicates Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in Patients With Chronic Heart Failure; GDMT, guideline-directed medical treatment; HF, heart failure; INOVATE-HF, Increase of Vagal Tone in Heart Failure; L, left; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume; NA, not applicable; NECTAR-HF, Neural Cardiac Therapy for Heart Failure; NYHA, New York Heart Association class; and R, right. Reprinted from De Ferrari23 with permission of the publisher. Copyright © 2014, Springer Science+Business Media New York.Download figureDownload PowerPointFigure 3. Effect of vagal stimulation over time: (A) change after 6 months in left ventricular end-systolic volume index in 29 patients; (B) in LVEF after 1 year in 23 patients; and (C) change in the 6-minute walk test after 2 years in 19 patients. Reprinted from De Ferrari et al8 with permission of the publisher. Copyright © 2015, Oxford University Press.A different technical approach with an open loop VS system that did not have an right ventricular sensing lead was used in the Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in Patients With Chronic Heart Failure (ANTHEM-HF) study.20 This was an open-label phase II trial that enrolled 60 patients with NYHA class II and III HF, LVEF<40%, and QRS<150 ms, who were randomized to either left or right cervical VS. The stimulation intensity of VS was uptitrated during a 10-week period to reach 2.0±0.6 mA. The primary safety objective was the incidence of procedure and device-related complications. There were 2 coprimary efficacy end points: the first was LVEF, which, in the pooled analysis of right and left VS, increased by 4.5% (P<0.05). The relevance of this finding, however, is mitigated by the absence of significant change in the second end point, LV end-systolic volume, which decreased nonsignificantly by 4.1 mL. Although there was a trend toward greater improvement with right VS, these differences were not statistically significant (Figure 4). Overall, 77% of patients improved by at least 1 NYHA class at 6 months, with a significant improvement in the MLwHF score.Download figureDownload PowerPointFigure 4. Mean and 95% confidence intervals of echocardiographic changes after 6 months of autonomic regulation therapy (overall, left-side treatment, and right-side treatment). LVEF indicates left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVESD, left ventricular end-systolic diameter. Reprinted from Premchand et al20 with permission of the publisher. Copyright @ 2014, Elsevier Inc.The Neural Cardiac Therapy for Heart Failure (NECTAR-HF) study was a phase II study enrolling patients with NYHA class II and III HF, an LVEF<35%, a QRS<130 ms, and LV end-diastolic diameter >55 mm. All 96 enrolled patients received a device implant and were randomized 2:1 to active treatment or sham treatment (with activation of the device only during the titration visits) for the first 6 months; thereafter, all patients received active treatment. The device used in NECTAR-HF also used a helical bipolar electrode and lacked an intracardiac right ventricular sensing lead, thus not allowing any regulation of stimulation on the basis of heart rate. The stimulation intensity was 1.4±0.8 mA. The primary efficacy end point, which was the change in LV end-systolic diameter at 6-month follow-up, was not significantly different (P=0.60) in the treatment and the control group.21,24 Additional secondary end points, including LV end-diastolic dimension, LV end-systolic volume, LVEF, peak VO2, and N-terminal of the prohormone brain natriuretic peptide, were not different between groups. However, there were statistically significant improvements in quality of life for the MLwHF Questionnaire (P=0.049) and the NYHA class (P=0.032) in the therapy group. Importantly, an assessment of blinding performed at 6 months revealed that 70% of the patients assigned to active treatment correctly guessed their randomization group, which was likely secondary to side effects of VS with this device.The discrepancies in findings among the 3 VS studies warrant further discussion. A first issue is that each study used a different VS device. Whereas 2 of the devices were open-loop systems that were designed to treat patients with epilepsy, the VS device used in the CardioFit pilot trial was a closed-loop system that was designed for the treatment of HF. Probably, the most important issue is that each study used a different stimulation protocol and especially a different stimulation intensity and frequency. In agreement with the fact that lower frequencies allow greater amplitudes to be reached with tolerable side effects, the stimulation intensity did vary in the 3 studies being 1.3±08 mA in NECTAR-HF (range, 0.3–3.5), 2.0±0.6 mA in ANTHEM-HF (maximum intensity, 3 mA), and 4.2±1.2 mA in the CardioFit pilot trial (range, 1.1–5.5). With increases in stimulation intensity, the number of recruited vagus nerve fibers is progressively higher. Canine experimental studies have shown that intensities, such as those used in the NECTAR-HF study, albeit providing an improvement in LV function,25 recruit only a minority of the fibers in the cervical vagus trunk.26 Thus, it is likely that the lower intensity of VS in NECTAR-HF and ANTHEM-HF was not sufficient to adequately activate vagal fibers and that this could explain the different results. Finally, these differences may have been favored by the small number of patients involved in the trials.The last VS clinical trial, which is still ongoing, is the Increase of Vagal Tone in Heart Failure (INOVATE-HF), which is an international, multicenter, randomized clinical trial designed to assess safety and efficacy of VS using the CardioFit system in patients with symptomatic HF who are on GDMT.22 INOVATE-HF is randomizing 650 patients with NYHA class III symptoms, an LVEF ≤40% and LV end-diastolic dimensions 50 to 80 mm in a 3:2 ratio to either active treatment (implanted) or continuation of medical therapy (not implanted). The primary end point of the study is the composite of all-cause mortality or unplanned HF hospitalization equivalent, using a time to first event analysis. There are 2 coprimary safety end points: freedom from procedure and system-related complication events at 90 days and number of patients with all-cause death or complications at 12 months. This trial will complete enrollment in the first quarter of 2015.Spinal Cord StimulationThe concept for SCS originated following the revolutionary gate theory for the origin of pain, which suggested the possibility of suppressing pain by closing the gate through activation of large diameter afferent fibers.27,28 Although the mechanisms of action of SCS are not completely understood, it seems that the mechanism of analgesia when SCS is applied in neuropathic pain states may be different from that involved in analgesia for peripheral ischemia.29 In neuropathic pain states, experimental evidence shows that SCS alters the local neurochemistry in the dorsal horn, suppressing neuronal hyperexcitability, presumably by affecting the local concentration of several neurotransmitters and neuromodulators, most notably by increasing the levels of γ-aminobutyric acid.30 However, in case of peripheral ischemic pain, analgesia seems to derive mostly from peripheral vasodilatation. Relevant here, SCS can be used for the treatment of refractory angina pectoris, in the absence of change in cardiovascular hemodynamics.31 An antiadrenergic effect was thought to mediate the marked reduction in infarct size produced by prophylactic SCS, because this effect was blocked by α- or β-adrenergic blocking agents.32 Olgin et al33 suggested that SCS at the T1 to T2 level enhanced parasympathetic activity. SCS increased sinus cycle length and the AH interval, an effect that was abolished by bilateral vagal transection, and reduced the occurrence of VT/VF from 59% to 23% in a canine model in which ventricular arrhythmias were elicited by transient myocardial ischemia.34 Subsequently, 28 dogs with HF induced by anterior myocardial infarction and rapid pacing were assigned for 5 weeks to no therapy, carvedilol, or SCS (delivered at T4/T5 region for 2 hours, 3× a day).35 LVEF, that had declined to 18% after the induction of HF, recovered to 28%, 34%, and 47%, respectively, in the control, carvedilol, and SCS groups. Similar findings were observed with SCS in a porcine animal model of ischemia and reperfusion.36Based on the above preclinical models, several clinical studies have been conducted in patients with HF. The Spinal Cord Stimulation for Heart Failure (SCS HEART) study37 implanted a SCS device in 17 patients with NYHA class III HF, programmed to provide SCS for 24 hours a day (50 Hz at pulse width 200 μs). Patient safety was the primary end point of the study. Three patients required device reprogramming or repositioning because of back or neck discomfort. Significant improvements were observed at 6 months in NYHA class (2.1 versus 3.0), MLwHF Questionnaire (27±22 versus 42±26), LV end-systolic volume (137±37 versus 174±57 mL), and LVEF (37±8% versus 25±6%); overall 73% of patients had an improvement in ≥4 of 6 efficacy parameters. At 18-month follow-up, 2 patients (12%) died, 2 (12%) were hospitalized for HF and there continued to be no device–device interactions. Four patients (24%) with VT/VF before receiving the SCS therapy continued with VT/VF requiring implantable cardioverter defibrillator intervention, not confirming in this clinical setting the favorable antiarrhythmic effects observed in preclinical studies.34,35The limitations of a small nonrandomized study were highlighted by the recent presentation of the results of the Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure (DEFEAT-HF, NCT01112579), performed in 66 NYHA class III HF patients with a mean LVEF of 29±5%. Patients were randomized 3:2 to SCS or control, and after the 6-month visit, the control patients were crossed over to receive active therapy. The primary study end point was a reduction in the LV end-systolic volume index after 6 months of SCS therapy in the treatment arm versus the control arm. The results at 6 months show no difference between the active therapy arm and the control arm in LV end-systolic volume index, in peak VO2, in N-terminal of the prohormone brain natriuretic peptide, and in all other parameters. The 12-month follow-up visit data will assess the effects of SCS for those enrolled in the therapy arm for a year, as well as the effects of SCS treatment for 6 months for those randomized from the control group to SCS treatment at 6 months.After the negative results of the controlled study, it is presently unclear whether a phase III trial using this approach in patients with systolic HF will ever be performed.Renal DenervationAutonomic neural regulation of renal function has received increased attention during the past few years following the reports that catheter-based renal denervation could be safely performed by either radiofrequency energy or ultrasound delivery, thus representing a potentially useful procedure in all conditions associated with increased sympathetic activity. The renal sympathetic nervous system comprises both efferent and afferent renal nerves lying within and immediately adjacent to the wall of the renal artery. Although renal efferent nerves are distributed widely throughout the renal vasculature, renal afferent nerves are mainly located in the pelvic area. Renal sympathetic nerve activity is modulated in the central nervous system where information arising from all the different sensory receptors (also including signaling from renal sensory nerve fibers) is integrated. Increases in efferent renal sympathetic nerve activity reduce renal blood flow and decrease excretion of urinary sodium by activation of α1-adrenoceptors, and increase renin secretion rate through activation of β1-adrenoceptors.Numerous studies have shown that increased renal efferent sympathetic activity plays an important role in the volume expansion that is observed in HF38 by provoking renin release and the consequent increase in circulating and brain levels of angiotensin II.39 HF also leads to diminished afferent renal sensory signaling, thereby blunting inhibitory reno-renal reflexes, which further contributes to increased renal sympathetic efferent activation.40 In animal models, renal denervation improves volume-sensitive natriuresis, abolishes the decrease in mean renal blood flow and the increase in renal vascular resistance, and normalizes angiotensin II receptor expression.41 In rats with postischemic HF induced by coronary artery ligation, structural and functional remodelling was partially prevented in denervated animals when compared with the control animal.42 A still unsettled issue concerns the fact that reinnervation is expected to occur, soon or later, and it will also likely affect the afferent component of renal nerves.43In patients with HF, the norepinephrine spillover from heart and kidneys is increased44 and, specifically, increased renal sympathetic activity has been associated with all-cause mortality and heart transplants in these patients.45Although several studies have been conducted in drug-resistant hypertensive patients,46 the clinical experience with renal denervation in HF is far less. The REACH-Pilot study, the first-in-man in HF, evaluated 7 patients with symptomatic systolic HF (NYHA class III to IV) on maximal tolerated medical therapy.47 There were no procedural complications and no significant hemodynamic disturbances were noted during the acute phase post renal denervation. All patients described themselves as symptomatically improved and had an increase in the 6-minute walking test. No hypotensive or syncopal episodes were reported during the 6-month follow-up period. However, none of these HF patients had a systolic blood pressure below 120 mm Hg. Several clinical trials are currently under way to evaluate the effects of renal denervation in patients with systolic HF and lower entry systolic blood pressure (Table 2). Based on studies in hypertensive patients showing that renal denervation may reduce left ventricular mass and improve diastolic function, a multicenter randomized controlled trial (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction, DIASTOLE) has been initiated to determine whether renal denervation, on top of medical treatment, is superior to medical treatment alone in improving echocardiographic parameters of diastolic function in patients with HF with preserved LVEF and hypertension.48 Further studies in HF with preserved LVEF are listed in Table 2.Table 2. Characteristics of Trials With Renal Denervation in Heart FailureStudy/AcronymStudy DesignPatient CharacteristicPrimary OutcomeEstimated EnrollmentSystolic HFNCT02085668Renal Denervation in Patients with Chronic Heart FailureRandomized Open labelNYHA II–III, LVEF 10%–40%, GFR≥30 mL/min per 1.73 m2, BNP>100 pg/mL or NTproBNP>400 pg/mL, standard medical therapy, SBP>90 mm HgSafety of renal denervation with the SimplicityTM Catheter System, number of complications associated with the delivery and use of the SymplicityTM System100NCT01870310Renal Denervation in Patients with Heart Failure and Severe Left Ventricular DysfunctionRandomized Open labelNYHA II–IV, LVEF≤35%, standard medical therapy, SBP≥110 mm HgChange in serum NT-proBNP at 6 mo and 1 y from baseline in both groups50NCT01392196Renal Denervation in Patients with Severe Heart Failure and Renal Impairment Clinical Trial/SYMPLICITY-HFSingle group assignment Open labelNYHA II–IV, LVEF≤40%, GFR 30–75 mL/min per 1.73 m2, GDMT, SBP>90 mm HgSafety of renal denervation in patients with HF as measured by adverse events40NCT02099903Renal Denervation in Patients with Heart Failure Secondary to Chagas DiseaseRandomized Open labelHF secondary to Chagas’s disease, NYHA II–III, LVEF<40%, standard HF therapy, SBP>90 mm HgComposite: death, myocardial infarction, cerebrovascular event, need of intervention on renal arteries and renal function impairment (decrease in eGFR>30% from baseline)30NCT01954160Study of Renal Denervation in Patients With Heart Failure/PRESERVERandomized Open labelNYHA II–III, LVEF<40%, daily loop diuretic, GDMT, SBP≥110 mm HgWithin-subject comparison of increase in urine sodium excretion after saline loading before RSD and 13 wk after RSD64NCT01402726Renal Sympathetic Modification in Patients With Heart Failure/SWAN-HFNon-randomized Open labelNYHA II–IV, LVEF≤40% or ≥45%, eGFR≥45 mL/minComposite cardiovascular events200NCT01790906Renal Sympathetic Denervation for Patients With Chronic Heart Failure/RSD4CHFRandomized Single blindNYHA II–IV, LVEF≤35%All-cause mortality, cardiovascular events200Diastolic HFNCT02041130Renal Denervation in Heart Failure Patients with Preserved Ejection Fraction/RESPECT-HFRandomized Open labelNYHA II–IV LVEF≥50%, evidence of LV diastolic dysfunctionChanges in left atrial volume index (LAVi) and left ventricular mass index (LVMi) on cardiac MRI between baseline and 6 mo144NCT02115230Renal Denervation in Patients with Heart Failure with Normal LV FunctionRandomized Open labelHF with normal LV function, LV hypertrophy, hypertension treated with at least 2 antihypertensive drugsChange from baseline E/E′ at 12 mo+safety (composite of death, myocardial infarction, cerebrovascular events need of intervention on renal arteries, and renal function impairment)40NCT01583881DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection Fraction/DIASTOLE48Randomized Open labelLVEF≥50%, evidence of LV diastolic dysfunctionChange from baseline E/E′ at 12 mo60NCT01840059Renal Denervation in Heart Failure With Preserved Ejection Fraction/RDT-PEFRandomized Open l