Long-term safety and efficacy of renal sympathetic denervation in atrial fibrillation: 3-year results of the AFFORD study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia which has been associated with increased sympathetic nervous system activity and hypertension. Recent evidence indicated that renal sympathetic denervation (RDN) could safely contribute to an improvement in AF burden. OBJECTIVE: To investigate the long-term safety and efficacy of radiofrequency RDN in hypertensive patients with symptomatic AF. METHODS: This pilot study included patients with symptomatic paroxysmal or persistent AF (European Hearth Rhythm Association class ≥ II) despite optimal medical therapy, office systolic blood pressure (BP) ≥ 140 mmHg and ≥ 2 antihypertensive drugs. AF burden was measured using an implantable cardiac monitor (ICM), implanted 3 months prior to RDN. ICM interrogation and 24-h ambulatory BP monitoring were performed at baseline and at 3/6/12/24/36 months post RDN. The primary efficacy outcome was daily AF burden. Statistical analyses were performed using Poisson and negative binomial models. RESULTS: A total of 20 patients with a median age [25th-75th percentiles] of 66.2 [61.2-70.8] years (55% female) were included. At baseline, office BP ± standard deviation (SD) was 153.8/87.5 ± 15.2/10.4 mmHg, while mean 24-h ambulatory BP was 129.5/77.3 ± 15.5/9.3 mmHg. Baseline daily AF burden was 1.4 [0.0-10.9] minutes/day and throughout a 3-year follow-up period, no significant change was observed (- 15.4%/year; 95% confidence interval (CI) - 50.2%, + 43.7%; p = 0.54). The number of defined daily doses of antiarrhythmic drugs and antihypertensive drugs remained stable over time, while mean 24-h ambulatory systolic BP decreased with - 2.2 (95% CI - 3.9, - 0.6; p = 0.01) mmHg/year. CONCLUSIONS: In patients with hypertension and symptomatic AF, stand-alone RDN reduced BP but did not significantly reduce AF burden up until 3 years of follow-up.

Association between renal sympathetic denervation and arterial stiffness: the ASORAS study.

OBJECTIVES: Renal sympathetic denervation (RDN) reduces blood pressure (BP). However, one out of three patients does not exhibit a significant BP response to the therapy. This study investigates the association between noninvasive vascular stiffness indices and RDN-mediated BP reduction. METHODS: In this prospective, single-arm pilot study, patients with systolic office BP at least 140 mmHg, mean 24-h systolic ambulatory blood pressure (ABP) at least 130 mmHg and at least three prescribed antihypertensive drugs underwent radiofrequency RDN. The primary efficacy endpoint was temporal evolution of mean 24-h systolic ABP throughout 1-year post RDN (measured at baseline and 3-6-12 months). Effect modification was studied for baseline ultrasound carotid-femoral and magnetic resonance (MR) pulse wave velocity (PWV), MR aortic distensibility, cardiac MR left ventricular parameters and clinical variables. Statistical analyses were performed using linear mixed-effects models, and effect modification was assessed using interaction terms. RESULTS: Thirty patients (mean age 62.5 ±â€Š10.7 years, 50% women) with mean 24-h ABP 146.7/80.8 ±â€Š13.7/12.0 mmHg were enrolled. Following RDN, mean 24-h systolic ABP changed with -8.4 (95% CI: -14.5 to -2.3) mmHg/year ( P  = 0.007). Independent effect modifiers were CF-PWV [+2.7 (0.3 to 5.1) mmHg/year change in outcome for every m/s increase in CF-PWV; P  = 0.03], daytime diastolic ABP [-0.4 (-0.8 to 0.0) mmHg/year per mmHg; P  = 0.03], age [+0.6 (0.2 to 1.0) mmHg/year per year of age; P  = 0.006], female sex [-14.0 (-23.1 to -5.0) mmHg/year as compared with men; P  = 0.003] and BMI [+1.2 (0.1 to 2.2) mmHg/year per kg/m 2 ; P  = 0.04]. CONCLUSION: Higher CF-PWV at baseline was associated with a smaller reduction in systolic ABP following RDN. These findings could contribute to improve identification of RDN responders.

Long-term follow-up of patients undergoing renal sympathetic denervation.

OBJECTIVES: Renal denervation (RDN) proved to significantly lower blood pressure (BP) at 2-6 months in patients on and off antihypertensive drugs. Given a lack of longer-term follow-up data, our aim was to assess the safety and efficacy of RDN up to five years taking into account antihypertensive drug regimen changes over time. METHODS: In the present single-center study, patients underwent RDN for (therapy resistant) hypertension. Patients underwent protocolized yearly follow-up out to five years. Data were collected on 24-h ambulatory BP and office BP monitoring, renal function, antihypertensive drug regimen, and safety events, including non-invasive renal artery imaging at 6/12 months. Efficacy analyses were performed using linear mixed-effects models. RESULTS: Seventy-two patients with mean age 63.3 ± 9.5 (SD) years (51% female) were included. Median follow-up time was 3.5 years and Clark's Completeness Index was 72%. Baseline ambulatory daytime BP was 146.1/83.7 ± 17.4/12.2 mmHg under a mean number of 4.9 ± 2.7 defined daily doses (DDD). At five years, ambulatory daytime systolic BP as calculated from the mixed model was 120.8 (95% CI 114.2-127.5) mmHg and diastolic BP was 73.3 (95% CI 69.4-77.3) mmHg, implying a reduction of -20.9/-8.3 mmHg as compared to baseline estimates (p < 0.0001). The number of DDDs remained stable over time (p = 0.87). No procedure-related major adverse events resulting in long-term consequences were observed. CONCLUSIONS: The BP-lowering effect of RDN was safely maintained at least five years post-procedure as reflected by a significant decrease in ambulatory daytime BP in the absence of escalating antihypertensive drug therapy over time.

Effect of renal denervation on catecholamines and the renin-angiotensin-aldosterone system.

INTRODUCTION: The effect of renal sympathetic denervation (RDN) on neurohormonal responses is largely unknown. We aimed to assess the effect of RDN on the renin-angiotensin-aldosterone system (RAAS) and endogenous catecholamines. METHODS: A total of 60 patients with hypertension underwent RDN and remained on a stable antihypertensive drug regimen. Samples for plasma aldosterone, plasma renin and urine (nor)metanephrine were collected at baseline and at 6 months post procedure. Ambulatory blood pressure (BP) recordings were obtained at baseline and at 6 months post procedure. RESULTS: Mean age was 64±9 years, and 30/60 patients were male. At 6 months, average daytime systolic and diastolic ambulatory BP decreased by 10 and 6 mmHg, respectively (p<0.001). No significant change was observed in plasma aldosterone (median=248.0 pmol/L (interquartile range (IQR) 113.3-369.5 pmol/L) vs. median=233.0 pmol/L (IQR 110.3-360.8 pmol/L); p=0.66); renin (median=19.5 µIU/mL (IQR 6.8-119.5 µIU/mL) vs. median=14.3 µIU/mL (IQR 7.2-58.0 µIU/mL); p=0.32), urine metanephrine (median=0.46 µmol/L (IQR 0.24-0.77 µmol/L) vs. median=0.46 µmol/L (IQR 0.22-0.88 µmol/L); p=0.75) and normetanephrine (median=1.41 µmol/L (IQR 0.93-2.00 µmol/L vs. median =1.56 (IQR 0.74-2.50 µmol/L); p=0.58) between baseline and 6 months, respectively. No correlation was found between the decrease in mean systolic daytime BP and changes in RAAS hormones or endogenous catecholamines. CONCLUSION: Despite significant reductions in ambulatory BP, RDN did not result in a significant change in endogenous catecholamines or in RAAS hormones at 6 months.

Local myocardial stiffness variations identified by high frame rate shear wave echocardiography.

BACKGROUND: Shear waves are generated by the closure of the heart valves. Significant differences in shear wave velocity have been found recently between normal myocardium and disease models of diffusely increased muscle stiffness. In this study we correlate in vivo myocardial shear wave imaging (SWI) with presence of scarred tissue, as model for local increase of stiffness. Stiffness variation is hypothesized to appear as velocity variation. METHODS: Ten healthy volunteers (group 1), 10 hypertrophic cardiomyopathy (HCM) patients without any cardiac intervention (group 2), and 10 HCM patients with prior septal reduction therapy (group 3) underwent high frame rate tissue Doppler echocardiography. The SW in the interventricular septum after aortic valve closure was mapped along two M-mode lines, in the inner and outer layer. RESULTS: We compared SWI to 3D echocardiography and strain imaging. In groups 1 and 2, no change in velocity was detected. In group 3, 8/10 patients showed a variation in SW velocity. All three patients having transmural scar showed a simultaneous velocity variation in both layers. Out of six patients with endocardial scar, five showed variations in the inner layer. CONCLUSION: Local variations in stiffness, with myocardial remodeling post septal reduction therapy as model, can be detected by a local variation in the propagation velocity of naturally occurring shear waves.

Clinical Applicability of Monitoring Antihypertensive Drug Levels in Blood.

Dried blood spot (DBS) analysis is a novel analytical method for therapeutic drug monitoring to identify nonadherence to antihypertensive drugs. This study was conducted to evaluate the clinical applicability of measuring drug concentrations of 8 antihypertensive drugs, using DBS and venipuncture. Furthermore, this study aimed to provide more insight into the between-patient variability in drug concentrations. False-negative values from DBS compared with a venipuncture were determined to assess drug adherence. A generalized estimating equation was used to estimate the model parameters, including sex, dose, age, weight, and the time interval, between drug intake and sampling, on the Cplasma (drug concentration in plasma). No false-negative values were found when measuring nonadherence using DBS compared with venipuncture. A high variability in Cplasma between patients was observed, especially at peak concentrations with a fold change reaching from 2.3 to 35.2. The time of intake was significantly related to the height of the Cplasma in 7 of the 8 measured drugs with a P<0.05, but the influence of dose, weight, age, and sex on drug levels differed largely between the measured drugs. DBS is a reliable and convenient method to assess nonadherence to antihypertensive drugs in clinical practice. The Cplasma of the 8 antihypertensive drugs in this study show a large interindividual difference, and therefore, low plasma concentrations do not necessarily mean nonadherence. Nonadherence can only be confirmed if drug levels are undetectable, that is, values below the lower limit of detection.

Using social media to recruit study participants for a randomized trial for hypertension.

Aims: The present study aimed to evaluate the potential of social media as an approach to recruit hypertensive subjects. Methods and results: In addition to conventional trial recruitment, Facebook ads were run. Over a 115-day recruitment period, Facebook reached 5.3 million people in 168 separate campaigns run in the proximity of 19 sites in the USA and 14 sites in Europe. A total of 182 839 participants (3.4%) clicked on the ad; of those 10 483 subjects (5.7%) completed a dedicated questionnaire. This resulted in 3632 potential candidates. A total of 285 potential candidates were recruited by various recruitment strategies in the specified time period, of which 184/285 (64.6%) came from Facebook. When comparing Facebook with a 7-day radio spot in the same time period, 48 radio spots were launched; resulting in nine inquiries with eventually five potential candidates and two consents. Conclusion: Targeted social media was a successful and efficient strategy to recruit hypertensive subjects.

Renal sympathetic denervation in patients with vasospastic angina.

BACKGROUND: Sympathetic overactivity has been linked to vasospastic angina (VSA), although the exact pathophysiology of VSA is poorly understood. The purpose of this study is to assess if renal sympathetic denervation (RDN) reduces cardiac sympathetic nerve activity with a subsequent beneficial effect on angina relief in patients with refractory VSA. METHODS AND RESULTS: Cardiac sympathetic nerve activity was assessed prior to procedure and at 6 months post-procedure using iodine-123 labeled meta-iodobenzylguanidine (123I-MIBG) imaging. The Seattle Angina questionnaire (SAQ) was used to assess the degree to which the disease impacts quality of life. No significant change was observed in early HMR (pre-RDN: 2.74 [2.10 to 3.21] vs 6 months post-RDN: 2.57 [2.20 to 3.00]; P = 0.76), and late HMR (pre-RDN: 2.56 [2.18 to 3.20] vs 6 months post-RDN: 2.36 [2.13 to 3.22]; P = 0.22). Additionally, no change was seen in WR (P = 0.22). SAQ results revealed significant improvements in perceived physical limitation, angina frequency, and quality of life at 6 months (P < 0.05 for all). CONCLUSION: RDN resulted in improvements in angina class and quality of life at 6 months in patients with refractory VSA. RDN, however, did not result in significant changes in cardiac sympathetic nerve activity as measured using 123I-MIBG. The latter observation should be considered with caution given the small sample size of this study. Larger studies are needed to assess this further.

Clinical Validation of a Dried Blood Spot Assay for 8 Antihypertensive Drugs and 4 Active Metabolites.

BACKGROUND: Drug nonadherence is one of the major challenges faced by resistant hypertension patients, and identification of this problem is needed for optimizing pharmacotherapy. Dried blood spot (DBS) sampling is a minimally invasive method designed to detect and determine the degree of nonadherence. In this study, a DBS method for qualifying 8 antihypertensive drugs (AHDs) and 4 active metabolites was developed and validated using ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). METHOD: The DBS assay was validated analytically and clinically, in accordance with FDA requirements. Analytical validation was accomplished using UHPLC-MS/MS. For clinical validation, paired peak and trough levels of DBS and plasma samples were simultaneously collected and comparatively analyzed using Deming regression and Bland-Altman analyses. All concentrations below the set lower limit were excluded. Deming regression analysis was used to predict comparison bias between the collected plasma and DBS samples, with DBS concentrations corrected accordingly. RESULTS: The UHPLC-MS/MS method for simultaneously measuring 8 AHDs and their metabolites in DBS, was successfully validated. With Deming regression no bias was observed in N = 1; constant bias was seen in N = 6 and proportional bias in N = 11 of the AHDs and metabolites. After correction for bias, only one metabolite (canrenone) met the 20% acceptance limit for quantification, after Bland-Altman analyses. In addition, amlodipine, valsartan, and [enalaprilate] met the 25% acceptance limit. CONCLUSIONS: A novel DBS assay for simultaneously qualifying and quantifying 8 AHDs and their metabolites, has been successfully developed and validated. The DBS assay is therefore a suitable method to detect drug nonadherence. However, with the exception of canrenone, the interchangeable use of plasma and DBS sampling to interpret drug quantities should be avoided.

Atrial fibrillation reduction by renal sympathetic denervation: 12 months' results of the AFFORD study.

AIM: The purpose of this pilot study was to assess whether renal sympathetic denervation (RDN) decreases atrial fibrillation (AF) burden in hypertensive patients with symptomatic AF at 6- and 12-month follow-up, as measured using an implantable cardiac monitor (ICM). METHODS AND RESULTS: A total of 20 patients with symptomatic paroxysmal or persistent AF (EHRA ≥ II) and primary hypertension with a mean office systolic blood pressure (BP) of > 140 mmHg were enrolled. After enrolment, an ICM was implanted 3 months pre-RDN to monitor AF burden. Quality of life (QOL) was assessed using the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. Mean age was 64 ± 7 years and 55% were females. AF burden in min/day decreased from a median (IQR) of 1.39 (0-11) pre-RDN to 0.67 (0-31.6) at 6 months (p = 0.64) and to 0.94 (0-6.0) at 12 months (pre-RDN vs. 12 months; p = 0.03). QOL improved significantly at both 6 months (+ 11 ± 15 points, p = 0.006) and 12 months (+ 10 ± 19, p = 0.04) as compared to pre-RDN. Office BP decreased significantly at 12-month follow-up (- 20 ± 19/- 7 ± 10 mmHg), p < 0.01) as compared to pre-RDN. Ambulatory BP decreased - 7 ± 16/- 3 ± 9 mmHg (p > 0.05) at 12-month follow-up as compared to pre-RDN. CONCLUSION: This pilot study suggests that RDN might be able to decrease AF burden in min/day as measured using an ICM, with a positive effect on QOL. Large-scale randomized trials are needed to prove the definite value of RDN in hypertensive patients with atrial fibrillation.

Safety and performance of diagnostic electrical mapping of renal nerves in hypertensive patients.

AIMS: The aim of this study was to evaluate the safety and performance of renal nerve stimulation (RNS) for diagnostic mapping of the renal nerves. METHODS AND RESULTS: In this first-in-man study, twenty hypertensive patients underwent RNS using the ConfidenHT system. Bilateral stimulations were performed at three to four sites per artery at 2 and 4 mA. The primary endpoint was change in systolic blood pressure (SBP). Mean office blood pressure was 156/89 mmHg. No periprocedural adverse events occurred. Stimulation with 2 mA resulted in a maximum change of 8.3±6.3 mmHg in SBP (based on 119 stimulations; p<0.001), while stimulating with 4 mA resulted in a maximum change of 10.1±7.8 mmHg (based on 61 stimulations; p<0.001). The mean change in SBP did not vary between mid, distal or branch sites when stimulating at 2 mA but was significantly higher at ostial (23±14 mmHg) than at non-ostial locations (9±7 mmHg) when stimulating at 4 mA (p=0.003). CONCLUSIONS: RNS can be performed safely and effectively along the renal artery and results in a large variation in temporary BP changes per patient and per anatomic location. RNS might help in optimising treatment effect and selecting potential responders to renal sympathetic denervation.

Prevalence and consequences of noncardiac incidental findings on preprocedural imaging in the workup for transcatheter aortic valve implantation, renal sympathetic denervation, or MitraClip implantation.

BACKGROUND: Dedicated data on the prevalence of incidental findings (IF) stratified according to overall clinical relevance and their subsequent correlation to outcome are lacking. The aim of the present study was to describe the prevalence and consequences of noncardiac IF on computed tomography or magnetic resonance imaging in the workup for interventional cardiovascular procedures. METHODS: A total of 916 patients underwent preprocedural computed tomography or magnetic resonance imaging in the workup for transcatheter aortic valve implantation (TAVI), renal sympathetic denervation (RDN), or MitraClip implantation. RESULTS: IF were found in 395 of 916 patients (43.1%), with an average of 1.8 IF per patient. Classifying the IF resulted in 155 patients with minor, 171 patients with moderate, and 69 patients with major IF. The intended procedure was delayed or canceled in only 15 of 916 (1.6%) of the patients because of the presence of potential malignant IF. In patients that did undergo the intended procedure (n = 774), the presence of a moderate or major IF (23.8%) did not impact 1-year mortality compared to no or minor IF (adjusted HR 0.90, 95% CI 0.56-1.44, P value = .65). These findings were consistent among patients referred for TAVI, RDN, or MitraClip. CONCLUSIONS: IF are frequent in patients referred for cardiovascular procedures. IF did not result in a delay or cancellation of the intended procedure in the vast majority of cases, irrespective of their clinical relevance. The presence of a major or moderate IF did not significantly impact 1-year mortality.

Therapeutic Drug Monitoring to Assess Drug Adherence in Assumed Resistant Hypertension: A Comparison With Directly Observed Therapy in 3 Nonadherent Patients.

Resistant hypertension is a common health problem leading to suboptimal cardiovascular prevention. A large number of patients with resistant hypertension have poor medication adherence explaining their assumed resistance to therapy. We combined directly observed therapy (DOT) with therapeutic drug monitoring (TDM) in 3 patients at several time points to enable an extensive feedback on blood pressure (BP) and drug levels. BP was measured with an automatic oscillatory device at regular intervals of 5 minutes (directly before and after drug intake) and at 30-minute intervals (at night) during admission. Blood samples were obtained at different time points (t = in hours; t = 0, 2, 4, 6, 12, and 24 hours after drug intake). DOT was performed under supervision of the physician. In 2 of the 3 patients, automated BP decreased directly after DOT, -10/0 and -5/-5 mm Hg, respectively. Plasma drug levels for several drugs or active metabolites were 0 at t = 0, whereas plasma levels were positive at t = 24 hours after observed intake. We recommend a more frequent use of TDM combined with repeated BP measurements in clinical practice because this is a convenient, objective method of measurement and to ensure that actual drug levels reflect the BP at the time of measurement.

Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.

BACKGROUND: Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications. METHODS: RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic-diastolic hypertension aged 18-75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426. FINDINGS: Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (-8·5 mm Hg, SD 9·3) than with the sham procedure (-2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: -6·3 mm Hg, 95% CI -9·4 to -3·1, p=0·0001). No major adverse events were reported in either group. INTERPRETATION: Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications. FUNDING: ReCor Medical.

Effect of catheter-based renal denervation on left ventricular function, mass and (un)twist with two-dimensional speckle tracking echocardiography.

BACKGROUND: Speckle tracking echocardiography (STE) is an echocardiography modality that is able to measure left ventricular (LV) characteristics, including rotation, strain and strain rate. Strain measures myocardial fibre contraction and relaxation. This study aims to assess the effect of renal sympathetic denervation (RDN) on functional myocardial parameters, including STE, and to identify potential differences between responders and non-responders. METHODS: The study population consisted of 31 consecutive patients undergoing RDN in the context of treatment for resistant hypertension. Patients were included between December 2012 and June 2014. Transthoracic echocardiography and speckle tracking analysis was performed at baseline and at 6 months follow-up. RESULTS: The study population consisted of 31 patients with treatment-resistant hypertension treated with RDN (mean age 64 ± 10 years, 15 men). The total study population could be divided into responders (n = 19) and non-responders (n = 12) following RDN. RDN reduced office blood pressure by 18.9 ± 26.8/8.5 ± 13.5 mmHg (p < 0.001). A significant decrease was seen in LV posterior wall thickness (LVPWd) (0.47 ± 1.0 mm; p = 0.020), without a significant change in the LV mass index (LVMI). In the total cohort, only peak late diastolic filling velocity (A-wave velocity) decreased significantly by 5.3 ± 13.2 cm/s (p = 0.044) and peak untwisting velocity decreased significantly by 14.5 ± 28.9°/s (p = 0.025). CONCLUSION: RDN reduced blood pressure and significantly improved functional myocardial parameters such as A-wave velocity and peak untwisting velocity in patients with treatment-resistant hypertension, suggesting a potential beneficial effect of RDN on myocardial mechanics.