Risk factors for developing pacing induced LV dysfunction: Experience from a tertiary center in the UK.

BACKGROUND: The risk factors for developing pacing induced left ventricular dysfunction (LVD) in patients with high burden of right ventricular pacing (RVP) is poorly understood. Therefore, in the present study, we aimed to assess the determinants of pacing induced LVD. METHODS: Our data were retrospectively collected from 146 patients with RVP > 40% who underwent generator change (GC) or cardiac resynchronization therapy (CRT) upgrade between 2016 and 2019 who had left ventricular ejection fraction (EF) ≥50% at initial implant. RESULTS: A total of 75 patients had CRT upgrade due to pacing induced LVD (EF < 50%) and 71 patients with preserved LV function (EF ≥ 50%) had a GC. Primary indication for pacing in both groups was complete heart block. Male predominance (p = .008), prior myocardial infarction (MI) (p = .001), atrial fibrillation (AF) (p = .009), chronic kidney disease (CKD) (p = .005), and borderline low systolic function (BLSF) (EF 50%-55%) (p = .04) were more prevalent in the CRT upgrade group. Presence of AF (odds ratio [OR] = 3.05, 95% confidence interval [CI] 1.42-6.58; p = .004), BLSF (OR = 3.8, 95% CI 1.22-11.8; p = .02), and male gender (OR = 2.41, 95% CI 1.14-5.08; p = .02) were independent predictors for RVP induced LVD. Age (OR = 1.08, 95% CI 1.02-1.14; p = .005) and BLSF (OR = 5.33, 95% CI 1.26-22.5; p = .023) were independent predictors of earlier development of LVD after implant. CONCLUSIONS: Our results suggested that AF, BLSF, and male gender are predictors for development of pacing induced LVD in patients with high RVP burden. LVD can occur at any time after pacemaker implant with BLSF and increasing age associated with earlier development of LVD.

Early pacemaker implantation for transcatheter aortic valve implantation is safe and effective.

BACKGROUND: Permanent pacemaker (PPM) implantation is a common complication of transcatheter aortic valve implantation (TAVI). The optimum timing of PPM implantation is still unclear as conduction abnormalities evolve and a balance needs to be struck between conservative delays in the hope of conduction recovery and overutilization of pacing. This study aimed to assess the safety and efficacy of early PPM implantation, without an observation period, among TAVI patients. METHODS: This is a retrospective, observational study of 1398 TAVI patients. Clinical and pacing data were collected at baseline, 30 days and at a median of 15 (4-21) months post-TAVI. Study endpoints included PPM-related complications, pacing utilization and hospital length of stay. RESULTS: One hundred five patients (8.2%) required a PPM, of which 13 were implanted pre and 92 post-TAVI. Seventy-six percent required pacing for either second- or third-degree heart block. Time to implantation for post-TAVI PPM was 1 (0-3) day. Six patients experienced a pacing-related complication- lead displacement (n = 3), hematoma (n = 2), and device infection (n = 1). Pacing utilization defined as pacing >10% of the time or a pacing requirement at the time of the pacing check was demonstrated in 83% of patients. Multivariate analysis revealed complete heart block (CHB) was the only independent predictor of pacing utilization. Hospital length of stay for the post-TAVI PPM group was longer than the group without PPM (4 [2-8] vs. 3 [2-4] days; p < .001). CONCLUSIONS: Early PPM implantation in TAVI patients is safe and majority of patients require pacing in the short and mid-term.

Cardiovascular changes during peanut-induced allergic reactions in human subjects.

BACKGROUND: Food allergy is the most common cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in nonfatal reactions remains poorly understood. OBJECTIVE: Our aim was to systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut. METHODS: Participants underwent double-blind placebo-controlled food challenge to peanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, and peripheral blood flow) and electrocardiogram findings during food challenges were assessed using noninvasive continuous monitoring. RESULTS: A total of 57 adults (median age 24 years [interquartile range = 20-29]), 53% of whom were female, participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease of 4.2% [95% CI = 0.8-7.6; P = .03]), heart rate (mean increase 11.6% [95% CI = 8.4-14.8; P < .0001]), and peripheral blood flow (mean increase 19.7% [95% CI = 10.8-28.6; P < .0001]), irrespective of reaction severity. These changes were reproduced at a subsequent repeat peanut challenge in 26 participants, and could be reversed with administration of intravenous fluids which resulted in faster resolution of abdominal symptoms. CONCLUSIONS: In this first detailed human study of cardiovascular changes during food-induced allergic reactions, we found evidence for significant fluid redistribution, independent of reaction severity. This provides a sound rationale for optimizing venous return during significant allergic reactions to food. Finally, these data provide a new paradigm for understanding severity in anaphylaxis, in which poor outcomes may occur as a result of a failure in compensatory mechanisms.

Post-operative cardiac implantable electronic devices in patients undergoing cardiac surgery: a contemporary experience.

AIMS: Optimum timing of pacemaker implantation following cardiac surgery is a clinical challenge. European and American guidelines recommend observation, to assess recovery of atrioventricular block (AVB) (up to 7 days) and sinus node (5 days to weeks) after cardiac surgery. This study aims to determine rates of cardiac implantable electronic devices (CIEDs) implants post-surgery at a high-volume tertiary centre over 3 years. Implant timing, patient characteristics and outcomes at 6 months including pacemaker utilization were assessed. METHODS AND RESULTS: All cardiac operations (n = 5950) were screened for CIED implantation following surgery, during the same admission, from 2015 to 2018. Data collection included patient, operative, and device characteristics; pacing utilization and complications at 6 months. A total of 250 (4.2%) implants occurred; 232 (3.9%) for bradycardia. Advanced age, infective endocarditis, left ventricle systolic impairment, and valve surgery were independent predictors for CIED implants (P < 0.0001). Relative risk (RR) of CIED implants and proportion of AVB increased with valve numbers operated (single-triple) vs. non-valve surgery: RR 5.4 (95% CI 3.9-7.6)-21.0 (11.4-38.9) CIEDs. Follow-up pacing utilization data were available in 91%. Significant utilization occurred in 82% and underutilization (<1% A and V paced) in 18%. There were no significant differences comparing utilization rates in early (≤day 5 post-operatively) vs. late implants (P = 0.55). CONCLUSION: Multi-valve surgery has a particularly high incidence of CIED implants (14.9% double, 25.6% triple valve). Age, left ventricle systolic impairment, endocarditis, and valve surgery were independent predictors of CIED implants. Device underutilization was infrequent and uninfluenced by implant timing. Early implantation (≤5 days) should be considered in AVB post-multi-valve surgery.

The effect of head-up tilt upon markers of heart rate variability in patients with atrial fibrillation.

BACKGROUND: Heart rate variability (HRV) analysis is uncommonly undertaken in patients with atrial fibrillation (AF) due to an assumption that ventricular response is random. We sought to determine the effects of head-up tilt (HUT), a stimulus known to elicit an autonomic response, on HRV in patients with AF; we contrasted the findings with those of patients in sinus rhythm (SR). METHODS: Consecutive, clinically indicated tilt tests were examined for 207 patients: 176 in SR, 31 in AF. Patients in AF were compared to an age-matched SR cohort (n = 69). Five minute windows immediately before and after tilting were analyzed using time-domain, frequency-domain and nonlinear HRV parameters. Continuous, noninvasive assessment of blood pressure, heart rate and stroke volume were available in the majority of patients. RESULTS: There were significant differences at baseline in all HRV parameters between AF and age matched SR. HUT produced significant hemodynamic changes, regardless of cardiac rhythm. Coincident with these hemodynamic changes, patients in AF had a significant increase in median [quartile 1, 2] DFA-α2 (+0.14 [-0.03, 0.32], p < .005) and a decrease in sample entropy (-0.17 [-0.50, -0.01], p < .005). CONCLUSION: In the SR cohort, increasing age was associated with fewer HRV changes on tilting. Patients with AF had blunted HRV responses to tilting, mirroring those seen in an age matched SR group. It is feasible to measure HRV in patients with AF and the changes observed on HUT are comparable to those seen in patients in sinus rhythm.

Assessing the Eligibility Criteria in Phase III Randomized Controlled Trials of Drug Therapy in Heart Failure With Preserved Ejection Fraction: The Critical Play-Off Between a "Pure" Patient Phenotype and the Generalizability of Trial Findings.

AIMS: To investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype, and survival. METHODS AND RESULTS: We applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real-life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials. CONCLUSIONS: Trial eligibility criteria have become stricter with time, which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality.

Gene therapy in heart failure. SERCA2a as a therapeutic target.

The treatment of heart failure (HF) may be entering a new era with clinical trials currently assessing the value of gene therapy as a novel therapeutic strategy. If these trials demonstrate efficacy then a new avenue of potential treatments could become available to the clinicians treating HF. In principle, gene therapy allows us to directly target the underlying molecular abnormalities seen in the failing myocyte. In this review we discuss the fundamentals of gene therapy and the challenges of delivering it to patients with HF. The molecular abnormalities underlying HF are discussed along with potential targets for gene therapy, focusing on SERCA2a. We discuss the laboratory and early clinical evidence for the benefit of SERCA2a gene therapy in HF. Finally, we discuss the ongoing clinical trials of SERCA2a gene therapy and possible future directions for this treatment.

Circulating plasma and platelet 5-hydroxytryptamine in carcinoid heart disease: a pilot study.

BACKGROUND AND AIM OF THE STUDY: Carcinoid heart disease (CaHD) is a rare form of valvular heart disease in patients with carcinoid syndrome (CS). The role of 5-hydroxytryptamine (5-HT) in the pathogenesis of CaHD is unclear. The study aim was to evaluate the association between platelet 5-HT (5-HTplt) and plasma 5-HT (5-HTpls) and valvular dysfunction. METHODS: Twelve patients with CaHD, 18 with CS and 10 'normal' subjects were recruited. Patients with CaHD underwent cardiac catheterization and echocardiography. 5-HTplt and 5-HTpls was sampled in blood from the femoral vein, right and left ventricle, and left antecubital fossa vein. RESULTS: Levels of 5-HTpls and 5-HTplt were significantly higher in patients with CaHD (median 5-HTpls 325 nmol/l and 5-HTplt 18.9 nmol/10(9) platelets) and CS (median 5-HTpls 155 nmol/l and 5-HTplt 16.4 nmol/10(9) platelets) when compared to healthy controls (median 5-HTpls 9 nmol/l and 5-HTplt 3.7 nmol/10(9) platelets; p < 0.0001 and p = 0.003, respectively). There was a significant increase in 5-HTplt and 5-HTpls between the femoral vein and right heart (p = 0.007 and p = 0.0002, respectively). There was no significant difference in 5-HTplt or 5-HTpls between the right and left side of the heart, irrespective of the presence of a patent foramen ovale or of left-sided CaHD. CONCLUSION: Plasma and platelet 5-HT levels are elevated in patients with CaHD. Despite exposure to similar levels of intracardiac plasma and platelet 5-HT, the development of valve dysfunction is heterogeneous. This suggests that individual heart valves have a susceptibility to the development of valvular dysfunction which is not related solely to plasma or platelet 5-HT levels.

Risk stratification in asymptomatic severe aortic stenosis: a critical appraisal.

Aortic stenosis is one of the most common forms of acquired valvular heart disease. The development of symptoms, namely syncope, angina, or heart failure, in patients with severe aortic stenosis predicts a high likelihood of mortality. Aortic valve replacement is the current standard of care. In truly asymptomatic patients, the risk of sudden death is perceived to be low; therefore many advocate conservative management of these patients until symptoms develop. Emerging data suggest that certain markers may identify subsets of asymptomatic patients who are at a high risk of cardiac events. This review critically appraises the growing plethora of adverse prognostic markers that have been identified and evaluates how these parameters may influence clinical practice and potentially identify patients in whom early surgical intervention is warranted.

Real-world evidence in a national health service: results of the UK CardioMEMS HF System Post-Market Study.

AIMS: The CardioMEMS HF System Post-Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic-guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. METHODS AND RESULTS: COAST is a prospective, international, multicentre, open-label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic-guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system-related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72-88%] than the previous 12 months (0.27 vs. 1.52 events/patient-year, respectively, P < 0.0001). Freedom from device/system-related complications and pressure sensor failure at 2 years was 100% and 99%, respectively. CONCLUSIONS: Remote haemodynamic-guided HF management, using frequent assessment of pulmonary artery pressures, was successfully implemented at 14 specialist centres in the UK. Haemodynamic-guided HF management was safe and significantly reduced hospitalization in a group of high-risk patients. These results support implementation of this innovative remote management strategy to improve outcome for patients with symptomatic HF. Clinical registration number: ClinicalTrials.gov identifier: NCT02954341.

Impact on survival of combination inhalers in patients with COPD at high risk of cardiovascular events.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular disease often co-exist and are both leading causes of death worldwide. Published data have previously suggested trends toward improved survival for patients taking long-acting ß agonists combined with inhaled corticosteroids (LABA-ICS) through beneficial actions on the respiratory and cardiovascular systems. We sought to explore this in a real-world setting. METHODS: A population-based longitudinal propensity score-matched cohort study was conducted in the United Kingdom, 1998-2015. Patients were identified from the Clinical Practice Research Datalink (CPRD) which is linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records. All patients had a validated diagnosis of COPD and were at high risk for cardiovascular events (history of myocardial infarction, diabetes mellitus, ischaemic heart disease, stroke and peripheral arterial disease). The primary outcome was all-cause mortality. RESULTS: The treatment group was composed of 2687 new users of LABA-ICS with COPD and comparisons were made in a control population of 2687 COPD patients prescribed LABAs alone. At three years follow-up death occurred in 358 (13.3%) patients in the treatment group and 427 (15.9%) patients in the control group. The use of LABA-ICS was modestly associated with improved survival compared to use of LABAs (hazard ratio 0.82, 95% CI 0.71-0.95, P = 0.007). CONCLUSIONS: Among patients with COPD with either established cardiovascular disease or at high risk of an index cardiovascular event, LABA-ICS inhaled therapy, compared with LABAs alone, was associated with a significantly improved survival.

A Novel Quadripolar Active Fixation Left-Ventricular Pacing Lead for Cardiac Resynchronization Therapy: Initial United Kingdom Experience.

OBJECTIVES: This study sought to assess immediate and short-term performance of the Medtronic Attain Stability Quadripolar 4798 lead (Medtronic, Dublin, Ireland). BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment for appropriately selected patients with left ventricular (LV) systolic dysfunction. The most common reason for failure to implant a lead is the lack of a suitable epicardial vein, due either to an absent vessel in the target site, an unacceptably high threshold, lead instability, phrenic nerve stimulation, or a combination of reasons. In August 2017, a novel quadripolar active fixation LV lead (Medtronic) was released. This paper reports the initial clinical experience with lead implantation and specifically immediate and short-term pacing parameters across 3 United Kingdom centers. METHODS: Consecutive patients eligible for CRT were deemed suitable for this lead. Immediate and short-term lead performance data regarding LV threshold, impedance, and displacement rates were collected at standard pacing checks (1 day, 5 weeks, 3 months, and 9 months post-implantation). RESULTS: CRT using this lead was attempted in 82 cases and was successful in 81 cases (98.8%). LV thresholds and impedance levels were 1.22 ± 0.75 V and 737 ± 319 Ω at implantation; 1.16 ± 0.71 V and 597 ± 218 Ω at day 1; 1.02 ± 0.48 V and 579 ± 148 Ω at week 6; 0.98 ± 0.49 V and 569 ± 133 Ω at 3 months; and 1.06 ± 0.48 V and 570 ± 140 Ω at 9 months. As of the publication of this paper, no LV lead has been displaced. CONCLUSIONS: CRT using the Medtronic lead was successful in more than 98% of the patients. Short-to-medium-term data regarding lead performance and stability were excellent, with zero displacements as of the publication of this paper.

Caudal fluoroscopy to guide venous access for pacemaker device implantation: should this now be standard practice?

We describe a technique that uses both posterior-anterior and caudal fluoroscopy to achieve venous access for pacemaker device implantation. A significant advantage of this technique is the ability to clearly demarcate both the anatomy of venous drainage and the lung border. We would encourage all centres to adopt this technique as a safe approach to venous access.

Effects of renal denervation on vascular remodelling in patients with heart failure and preserved ejection fraction: A randomised control trial.

OBJECTIVE: To assess the effect of renal denervation (RDT) on micro- and macro-vascular function in patients with heart failure with preserved ejection fraction (HFpEF). DESIGN: A prospective, randomised, open-controlled trial with blinded end-point analysis. SETTING: A single-centre London teaching hospital. PARTICIPANTS: Twenty-five patients with HFpEF who were recruited into the RDT-PEF trial. MAIN OUTCOME MEASURES: Macro-vascular: 24-h ambulatory pulse pressure, aorta distensibilty (from cardiac magnetic resonance imaging (CMR), aorta pulse wave velocity (CMR), augmentation index (peripheral tonometry) and renal artery blood flow indices (renal MR). Micro-vascular: endothelial function (peripheral tonometry) and urine microalbuminuria. RESULTS: At baseline, 15 patients were normotensive, 9 were hypertensive and 1 was hypotensive. RDT did not lower any of the blood pressure indices. Though there was evidence of abnormal vascular function at rest, RDT did not affect these at 3 or 12 months follow-up. CONCLUSIONS: RDT did not improve markers of macro- and micro-vascular function.

Improving the management of iron deficiency in ambulatory heart failure patients.

Based on clinical trial data patients with heart failure (HF) and evidence of iron deficiency should be offered intravenous (iv) iron with the aim of improving exercise capacity and symptoms. Baseline measurement in outpatient HF clinics demonstrated that only 50% of patients who may be eligible for iv iron were investigated with iron studies. Our aim was to make sure that 90% of the patients attending our heart failure clinics who were symptomatic and had an ejection fraction (EF) ≤45% should have their iron studies checked within the last six months. In an effort to increase the proportion of suitable patients in whom iron studies are requested, we carried out three plan-do-study-act (PDSA) cycles each with a different intervention. These interventions included a presentation of the clinical trial evidence at a HF multidisciplinary meeting, email reminders prior to clinic and stickers in the patient notes (repeated twice). The effect of each intervention was measured with the outcome being the proportion of eligible patients in whom iron studies were documented within the previous 6 months. The interventions increased the number of suitable patients who had iron studies checked, to as high as 100%, however this effect was not sustained. Root cause analysis revealed that clinicians were unenthusiastic to continue performing iron studies due to inefficiency in the process of admitting patients and giving them iv iron. For example median in-hospital stay of seven hours for an infusion that is given over 15 minutes. In an attempt to improve patient and physician satisfaction we piloted an ambulatory outpatient service to deliver iv iron. We demonstrated that this service was feasible and more efficient as less time was required waiting for a bed or spent in hospital and was less costly. In summary we have demonstrated interventions which can increase the identification of patients who would benefit from iv iron and piloted a new time and cost efficient system of administration of iv iron.

The evolving landscape of oral anti-arrhythmic prescriptions for atrial fibrillation in England: 1998-2014.

AIMS: An important decision in the management of patients with atrial fibrillation is whether to adopt a rate or rhythm control strategy. Options for the latter include oral membrane-active anti-arrhythmic drugs (AADs) or catheter ablation. Recent prescription trends may have been affected by the introduction of dronedarone and an increasing number of reports suggesting increased mortality in those taking AADs. We describe the trend in oral AAD prescriptions in England in the period 1998-2014. METHODS AND RESULTS: We conducted a retrospective study using data from the Prescription Cost Analysis system, which holds information on every prescription dispensed in the community in England. We obtained data from 1998 to October 2014 for all Class Ia, Ic, and III AADs. Amiodarone and sotalol remain the most commonly prescribed AADs in England, though the use of both is decreasing. There has been a linear increase in the uptake of flecainide. Dronedarone prescriptions peaked in 2011, and our most recent data show that amiodarone prescriptions are 25-fold those of dronedarone. CONCLUSION: There is a decline in the use of amiodarone and sotalol consistent with the growing safety concerns with these drugs along with neutral results from landmark trials comparing rate and rhythm control. Dronedarone has failed to make an impact on AAD prescribing. In contrast, flecainide has seen an increase in use during the study period.

Renal denervation in heart failure with preserved ejection fraction (RDT-PEF): a randomized controlled trial.

AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with increased sympathetic nervous system (SNS) tone. Attenuating the SNS with renal denervation (RDT) might be helpful and there are no data currently in humans with HFpEF. METHODS AND RESULTS: In this single-centre, randomized, open-controlled study we included 25 patients with HFpEF [preserved left ventricular (LV) ejection fraction, left atrial (LA) dilatation or LV hypertrophy and raised B-type natriuretic peptide (BNP) or echocardiographic assessment of filling pressures]. Patients were randomized (2:1) to RDT with the Symplicity™ catheter or continuing medical therapy. The primary success criterion was not met in that there were no differences between groups at 12 months for Minnesota Living with Heart Failure Questionnaire score, peak oxygen uptake (VO2 ) on exercise, BNP, E/e', LA volume index or LV mass index. A greater proportion of patients improved at 3 months in the RDT group with respect to VO2 peak (56% vs. 13%, P = 0.025) and E/e' (31% vs. 13%, P = 0.04). Change in estimated glomerular filtration rate was comparable between groups. Two patients required plain balloon angioplasty during the RDT procedure to treat renal artery wall oedema. CONCLUSION: This study was terminated early because of difficulties in recruitment and was underpowered to detect whether RD improved the endpoints of quality of life, exercise function, biomarkers, and left heart remodelling. The procedure was safe in patients with HFpEF, although two patients did require intraprocedure renal artery dilatation.

Renal denervation for the management of resistant hypertension.

Renal sympathetic denervation (RSD) as a therapy for patients with resistant hypertension has attracted great interest. The majority of studies in this field have demonstrated impressive reductions in blood pressure (BP). However, these trials were not randomized or sham-controlled and hence, the findings may have been overinflated due to trial biases. SYMPLICITY HTN-3 was the first randomized controlled trial to use a blinded sham-control and ambulatory BP monitoring. A surprise to many was that this study was neutral. Possible reasons for this neutrality include the fact that RSD may not be effective at lowering BP in man, RSD was not performed adequately due to limited operator experience, patients' adherence with their anti-hypertensive drugs may have changed during the trial period, and perhaps the intervention only works in certain subgroups that are yet to be identified. Future studies seeking to demonstrate efficacy of RSD should be designed as randomized blinded sham-controlled trials. The efficacy of RSD is in doubt, but many feel that its safety has been established through the thousands of patients in whom the procedure has been performed. Over 90% of these data, however, are for the Symplicity™ system and rarely extend beyond 12 months of follow-up. Long-term safety cannot be assumed with RSD and nor should it be assumed that if one catheter system is safe then all are. We hope that in the near future, with the benefit of well-designed clinical trials, the role of renal denervation in the management of hypertension will be established.