Renal artery and parenchymal changes after renal denervation: assessment by magnetic resonance angiography.

OBJECTIVES: Relatively little is known about the incidence of long-term renal damage after renal denervation (RDN), a potential new treatment for hypertension. In this study the incidence of renal artery and parenchymal changes, assessed with contrast-enhanced magnetic resonance angiography (MRA) after RDN, is investigated. METHODS: This study is an initiative of ENCOReD, a collaboration of hypertension expert centres. Patients in whom an MRA was performed before and after RDN were included. Scans were evaluated by two independent, blinded radiologists. Primary outcome was the change in renal artery morphology and parenchyma. RESULTS: MRAs from 96 patients were analysed. Before RDN, 41 renal anomalies were observed, of which 29 mostly mild renal artery stenoses. After a median time of 366 days post RDN, MRA showed a new stenosis (25-49% lumen reduction) in two patients and progression of pre-existing lumen reduction in a single patient. No other renal changes were observed and renal function remained stable. CONCLUSIONS: We observed new or progressed renal artery stenosis in three out of 96 patients, after a median time of 12 months post RDN (3.1%). Procedural angiographies showed that ablations were applied near the observed stenosis in only one of the three patients. KEY POINTS: • The incidence of vascular changes 12 months post RDN was 3.1%. • No renal vascular or parenchymal changes other than stenoses were observed. • Ablations were applied near the stenosis in only one of three patients.

Renal Denervation in a Real Life Setting: A Gradual Decrease in Home Blood Pressure.

OBJECTIVES: To investigate the blood pressure dynamics after renal denervation through monthly home blood pressure measurements throughout the first 12 months. METHODS: A cohort of 70 patients performed highly standardized monthly home blood pressure monitoring during the first year after denervation according to the European Society of Hypertension guidelines. At baseline and 12 months follow-up, office and ambulatory blood pressure as well as routine physical and laboratory assessment was performed. RESULTS: Home blood pressure decreased with a rate of 0.53 mmHg/month (95% CI 0.20 to 0.86) systolic and 0.26 mmHg/month (95% CI 0.08 to 0.44) diastolic throughout 12 months of follow-up, while the use of antihypertensive medication remained stable (+0.03 daily defined doses/month, 95% CI -0.01 to 0.08). On average, a 12 month reduction of 8.1 mmHg (95% CI 4.2 to 12.0) was achieved in home systolic blood pressure, 9.3 mmHg (95% CI -14.2 to -4.4) as measured by 24-hour ambulatory blood pressure monitoring and 15.9 mmHg (95% CI -23.8 to -7.9) on office measurements. CONCLUSION: Blood pressure reduction after renal denervation occurs as a gradual decrease that extends to at least one-year follow-up. Home monitoring seems a suitable alternative for ambulatory blood pressure monitoring after renal denervation.

Renal denervation in hypertensive patients not on blood pressure lowering drugs.

INTRODUCTION: Studies on the blood pressure lowering effect of renal denervation (RDN) in resistant hypertensive patients have produced conflicting results. Change in medication usage during the studies may be responsible for this inconsistency. To eliminate the effect of medication usage on blood pressure we focused on unmedicated hypertensive patients who underwent RDN. METHODS AND RESULTS: Our study reports on a cohort of patients, who were not on blood pressure lowering drugs at baseline and during follow-up, from eight tertiary centers. Data of patients were used when they were treated with RDN and had a baseline office systolic blood pressure (SBP) ≥140 mmHg and/or 24-h ambulatory SBP ≥130 mmHg. Our primary outcome was defined as change in office and 24-h SBP at 12 months after RDN, compared to baseline. Fifty-three patients were included. There were three different reasons for not using blood pressure lowering drugs: (1) documented intolerance or allergic reaction (57 %); (2) temporary cessation of medication for study purposes (28 %); and (3) reluctance to take antihypertensive drugs (15 %). Mean change in 24-h SBP was -5.7 mmHg [95 % confidence interval (CI) -11.0 to -0.4; p = 0.04]. Mean change in office SBP was -13.1 mmHg (95 % CI -20.4 to -5.7; p = 0.001). No changes were observed in other variables, such as eGFR, body-mass-index and urinary sodium excretion. CONCLUSION: This explorative study in hypertensive patients, who are not on blood pressure lowering drugs, suggests that at least in some patients RDN lowers blood pressure.

The Effects of Renal Denervation on Renal Hemodynamics and Renal Vasculature in a Porcine Model.

RATIONALE: Recently, the efficacy of renal denervation (RDN) has been debated. It is discussed whether RDN is able to adequately target the renal nerves. OBJECTIVE: We aimed to investigate how effective RDN was by means of functional hemodynamic measurements and nerve damage on histology. METHODS AND RESULTS: We performed hemodynamic measurements in both renal arteries of healthy pigs using a Doppler flow and pressure wire. Subsequently unilateral denervation was performed, followed by repeated bilateral hemodynamic measurements. Pigs were terminated directly after RDN or were followed for 3 weeks or 3 months after the procedure. After termination, both treated and control arteries were prepared for histology to evaluate vascular damage and nerve damage. Directly after RDN, resting renal blood flow tended to increase by 29±67% (P = 0.01). In contrast, renal resistance reserve increased from 1.74 (1.28) to 1.88 (1.17) (P = 0.02) during follow-up. Vascular histopathology showed that most nerves around the treated arteries were located outside the lesion areas (8±7 out of 55±25 (14%) nerves per pig were observed within a lesion area). Subsequently, a correlation was noted between a more impaired adventitia and a reduction in renal resistance reserve (ß: -0.33; P = 0.05) at three weeks of follow-up. CONCLUSION: Only a small minority of renal nerves was targeted after RDN. Furthermore, more severe adventitial damage was related to a reduction in renal resistance in the treated arteries at follow-up. These hemodynamic and histological observations may indicate that RDN did not sufficiently target the renal nerves. Potentially, this may explain the significant spread in the response after RDN.

Denervation of the renal arteries in metabolic syndrome: the DREAMS-study.

Chronic elevation of sympathetic nervous system is a key factor in metabolic syndrome. Because renal denervation (RDN) is thought to modulate sympathetic activity, we performed the Denervation of the Renal Arteries in Metabolic Syndrome (DREAMS)-study to investigate the effects of RDN on insulin sensitivity and blood pressure (BP) in patients with metabolic syndrome. Twenty-nine patients fulfilling the criteria for metabolic syndrome and who used a maximum of 1 antihypertensive or 1 antidiabetic drug or 1 of both gave informed consent and were treated by RDN. Glucose tolerance tests and 24-hour ambulatory BP measurements were performed at baseline, at 6 and 12 months of follow-up. Moreover, we performed self-monitored BP measurements at home every month. To assess sympathetic activity, we performed muscle sympathetic nerve activity and heart rate variability measurements at baseline and follow-up. The majority of the included patients was men (57%), mean body mass index was 31±5 kg/m(2). Median insulin sensitivity as assessed by the Simple Index assessing Insulin Sensitivity oral glucose tolerance test did not change at 6- and 12-month follow-up (P=0.60 and P=0.77, respectively). Mean 24-hour BP decreased by 6±12/5±7 mm Hg 12 months after RDN (P=0.04/0.01). However, self-monitored BP measurements data showed no reduction over time. Measurements of sympathetic activity showed no reduction in systemic sympathetic activity. In conclusion, RDN did not lead to a significant improvement of insulin sensitivity ≤12 months after treatment. Although a significant reduction in ambulatory BP was observed in this nearly drug-naïve population, the self-monitored BP measurements data suggest that this may be explained by regression to the mean. Moreover, no effect in systemic sympathetic activity was observed.

A systematic review concerning the relation between the sympathetic nervous system and heart failure with preserved left ventricular ejection fraction.

BACKGROUND: Heart failure with preserved left ventricular ejection fraction (HFPEF) affects about half of all patients diagnosed with heart failure. The pathophysiological aspect of this complex disease state has been extensively explored, yet it is still not fully understood. Since the sympathetic nervous system is related to the development of systolic HF, we hypothesized that an increased sympathetic nerve activation (SNA) is also related to the development of HFPEF. This review summarizes the available literature regarding the relation between HFPEF and SNA. METHODS AND RESULTS: Electronic databases and reference lists through April 2014 were searched resulting in 7722 unique articles. Three authors independently evaluated citation titles and abstracts, resulting in 77 articles reporting about the role of the sympathetic nervous system and HFPEF. Of these 77 articles, 15 were included for critical appraisal: 6 animal and 9 human studies. Based on the critical appraisal, we selected 9 articles (3 animal, 6 human) for further analysis. In all the animal studies, isoproterenol was administered to mimic an increased sympathetic activity. In human studies, different modalities for assessment of sympathetic activity were used. The studies selected for further evaluation reported a clear relation between HFPEF and SNA. CONCLUSION: Current literature confirms a relation between increased SNA and HFPEF. However, current literature is not able to distinguish whether enhanced SNA results in HFPEF, or HFPEF results in enhanced SNA. The most likely setting is a vicious circle in which HFPEF and SNA sustain each other.

Effects of renal denervation on end organ damage in hypertensive patients.

BACKGROUND: Renal denervation (RDN) is believed to reduce sympathetic nerve activity and is a potential treatment for resistant hypertension. The present study investigated the effects of RDN on end organ damage (EOD). DESIGN: The present study was a prospective cohort study (registered as NCT01427049). METHODS: Uncontrolled hypertensive patients underwent a work-up prior to and one year after RDN. Cardiac magnetic resonance (CMR) imaging was used to determine left ventricular (LV)-mass; pulse wave analysis and pulse wave velocity (PWV) were used for evaluation of central blood pressure (BP) and arterial stiffness and 24-hour urine was collected for assessment of urinary albumin excretion. The 24-hour ambulatory BP measurement (ABPM) was used to evaluate the effect of RDN on BP. RESULTS: Fifty-four patients gave informed consent for study participation. Mean age was 58 ± 10 years, 50% were male. One year after RDN, mean ABPM decreased by 7 ± 18/5 ± 11 mm Hg (p = 0.01/p < 0.01). In the patients followed-up in a standardised fashion ABPM decreased by 5 ± 18/4 ± 12 mm Hg (n = 34; p = 0.11/p = 0.09). Mean body surface area indexed LV-mass decreased by 3.3 ± 11.5 g/m(2) (corresponding to a 3 ± 11% reduction; p = 0.09). PWV increased by 2.9 (-2.2 to +6.1) m/s (p = 0.04). Augmentation index corrected for 75 beats per min did not change (median increase 3.0 (-7 to +17) mm Hg; p = 0.89). Urinary albumin excretion did not change during follow-up (mean decrease 10 ± 117 mg/24 hour; p = 0.61). CONCLUSION: In the current study, we observed a modest effect from renal denervation. Moreover, RDN did not result in a statistical significant effect on end organ damage 12 months after treatment.

The blood pressure-lowering effect of renal denervation is inversely related to kidney function.

OBJECTIVES: In renal denervation (RDN), a wide range in the blood pressure (BP)-lowering effect has been reported. On the basis of the current knowledge of pathophysiology, we hypothesized that the BP-lowering effect of RDN would be inversely related to kidney function. Second, we investigated whether direct and indirect variables of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) would be related as well. METHODS: Sixty-seven patients from a prospective cohort of patients treated with RDN with completed 6 months follow-up were included. Data collected during routine standardized work-up before RDN were used: 24-h urine excretion of creatinine, albumin, sodium and catecholamines, plasma creatinine, renin activity and aldosterone, ambulatory BP-monitoring and a captopril challenge test. When considered well tolerated, antihypertensive drugs were stopped before these investigations. RESULTS: The BP-lowering was inversely related to estimated glomerular filtration rate (eGFR) in patients who stopped antihypertensive drugs prior to testing (ß: 0.46, P = 0.013). There was a positive relation between SBP at baseline and the BP-lowering effect of RDN (ß:-0.55 mmHg per mmHg, P < 0.001). Parameters related to the rennin-angiotensin system (aldosterone, captopril test) and the sympathetic nervous system (dipping pattern and catecholamines in urine) positively related to the BP-lowering effect of RDN. CONCLUSION: The present explorative study shows an inverse relation between the BP-lowering effect of RDN and eGFR. Second, we found relations between variables of the RAAS and SNS with the BP-lowering effect of RDN. The data complement current concepts on pathophysiology of sympathetic hyperactivity and hypertension and may give some insight in the wide range of the effect of RDN.

Renal denervation in multiple renal arteries.

BACKGROUND: In most previous studies investigating efficacy of renal denervation (RDN), patients with multiple renal arteries are generally excluded from treatment. This study was designed to determine the prevalence of multiple renal arteries in patients referred for RDN, to propose a classification for anatomical eligibility and to investigate the relation between the presence of multiple arteries and blood pressure (BP)-lowering effect. MATERIALS AND METHODS: Patients referred for RDN who underwent noninvasive imaging of the renal arteries before treatment were included in present analysis. Eligible patients were treated. Renal function and BP were evaluated 6 months after treatment. RESULTS: Hundred and twenty-six patients referred for RDN were included in present analysis. Thirty-four per cent had multiple arteries. Sixty-nine patients underwent RDN. Office BP significantly reduced from 195 (± 26)/106 (± 14) mmHg to 165 (± 24)/95 (± 14) mmHg (P < 0·001). BP reduction in patients with multiple arteries which were all treated was comparable to patients with solitary arteries. However, patients with multiple which were not all treated showed a trend towards a less pronounced effect of RDN (ß: 11·6, P = 0·11). The proposed classification appeared useful by identifying eligible anatomy. Renal function at 6 months did not differ from baseline in all subgroups. CONCLUSIONS: Based on our results and the high prevalence of multiple arteries, it seems reasonable not to exclude patients with multiple renal arteries from RDN. Current analysis suggests that BP reduction may be less pronounced in patients with multiple renal arteries of whom not all arteries were treated.

Eligibility for renal denervation: experience at 11 European expert centers.

Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure-lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center's criteria was 42.5% (95% confidence interval, 38.0%-47.0%) and 39.7% (36.2%-43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.

Renal denervation in heart failure with normal left ventricular ejection fraction. Rationale and design of the DIASTOLE (DenervatIon of the renAl Sympathetic nerves in hearT failure with nOrmal Lv Ejection fraction) trial.

Aim Increasing evidence suggests an important role for hyperactivation of the sympathetic nervous system (SNS) in the clinical phenomena of heart failure with normal LVEF (HFNEF) and hypertension. Moreover, the level of renal sympathetic activation is directly related to the severity of heart failure. Since percutaneous renal denervation (pRDN) has been shown to be effective in modulating elevated SNS activity in patients with hypertension, it can be hypothesized that pRDN has a positive effect on HFNEF. The DIASTOLE trial will investigate whether renal sympathetic denervation influences parameters of HFNEF. Methods DIASTOLE is a multicentre, randomized controlled trial. Sixty patients, diagnosed with HFNEF and treated for hypertension, will be randomly allocated in a 1:1 ratio to undergo renal denervation on top of medical treatment (n = 30) or to maintain medical treatment alone (n = 30). The primary objective is to investigate the efficacy of pRDN by means of pulsed wave Doppler echocardiographic parameters. Secondary objectives include safety of pRDN and a comparison of changes in the following parameters after pRDN: LV mass, LV volume, LVEF, and left atrial volume as determined by magnetic resonance imaging. Also, MIBG (metaiodobenzylguanidine) uptake and washout, BNP levels, blood pressure, heart rate variability, exercise capacity, and quality of life will be assessed. Perspective DIASTOLE is a randomized controlled trial evaluating renal denervation as a treatment option for HFNEF. The results of the current trial will provide important information regarding the treatment of HFNEF, and therefore may have major impact on future therapeutic strategies. Trail registration NCT01583881.

Ischemia and reactive oxygen species in sympathetic hyperactivity states: a vicious cycle that can be interrupted by renal denervation?

Renal denervation has developed as a new treatment strategy for patients suffering from resistant hypertension. The success of this therapy is due to the fact that sympathetic hyperactivity is involved in the pathogenesis of elevated blood pressure. However, not only the sympathetic nervous system (SNS), but also the renin angiotensin system (RAS) is known to be involved in hypertension. In addition, RAS is involved in other sympathetic hyperactivity states, such as heart failure, chronic kidney disease, insulin resistance and obstructive sleep apnea. Moreover, renal denervation has a beneficial effect on patients suffering from these disease states. Recent research suggested that the production of reactive oxygen species (ROS) is elevated in sympathetic hyperactivity states, and that ROS are able to activate the SNS and local tissue renin angiotensin system. Therefore, this review discusses the possibility of ROS as a common trigger of SNS and RAS activity in sympathetic hyperactivity states, and the effect of renal denervation on this ROS production.

Eligibility for percutaneous renal denervation: the importance of a systematic screening.

OBJECTIVE: Percutaneous renal denervation (pRDN) is a new and promising therapy for resistant hypertension. Among patients suspected of having resistant hypertension, the actual presence of this condition needs to be well established; pseudoresistant hypertension and significant white-coat effect (WCE) should be excluded. This analysis presents the results of a standardized screening programme for patients referred for pRDN. METHODS: All patients referred to our centre for pRDN underwent a standardized stepwise screening and were subsequently discussed in a multidisciplinary team. The screening included a 24-h ambulatory blood pressure measurement (ABPM), collection of plasma, urine and saliva, and finally imaging of the renal arteries. RESULTS: From August 2010 till October 2012, 181 patients were referred for pRDN. Mean blood pressure (BP) was 182/100 mmHg, and median use was three antihypertensives. Ultimately, 121 patients (67%) were excluded from pRDN. Main reasons for exclusion were BP-related. Twenty-three patients (19%) had an office SBP less than 160 mmHg and 26 patients (22%) showed a WCE. Fourteen patients (12%) had a so far undetected underlying cause of hypertension, the majority being primary aldosteronism (n = 11). Nine patients had an ineligible renal anatomy. CONCLUSION: A high percentage of patients were excluded from treatment with pRDN due to secondary causes of hypertension, WCE or a BP below the currently advised thresholds. Treatment of these excluded patients would lead to inappropriate use of pRDN, leading most likely to little benefit for the patients and a burden to healthcare. Therefore, it is recommended to use a standardized screening before treatment with pRDN.