Abstract
Background/purpose
Catheter-based renal sympathetic denervation (RDN) has been introduced to lower blood pressure (BP) and sympathetic activity in patients with uncontrolled hypertension with at best equivocal results. It has been postulated that anatomic and procedural elements introduce unaccounted variability and yet little is known of the impact of renal anatomy and procedural parameters on BP response to RDN.
Methods/materials
Anatomical parameters such as length and diameter were analyzed by quantitative vascular analysis and the prevalence of accessory renal arteries and renal artery disease were documented in 150 patients with resistant hypertension undergoing bilateral RDN using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic).
Results
Accessory renal arteries and renal artery disease were present in 56 (37%) and 14 patients (9%), respectively. At 6-months, 24 h-ambulatory BP was reduced by 11/6 mm Hg ( p < 0.001 for both). Change of systolic blood pressure (SBP) was not related to the presence of accessory renal arteries ( p = 0.543) or renal artery disease ( p = 0.598). Patients with at least one main renal artery diameter ≤ 4 mm had a more pronounced reduction of 24 h-ambulatory SBP compared to patients where both arteries were >4 mm (−19 vs. −10 mmHg; p = 0.038). Neither the length of the renal artery nor the number of RF ablations influenced 24 h-ambulatory BP reduction at 6 months.
Conclusions
24 h-ambulatory BP lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, accessory arteries or renal artery disease. Further, there was no dose-response relationship observed with increasing number of ablations.
Condensed abstract
Because little is known of the impact of renal anatomy and procedural parameters on blood pressure (BP) response to renal denervation (RDN), anatomical and procedural data were analyzed in 150 patients undergoing bilateral RDN. BP lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, the presence of renal artery disease or accessory renal arteries. Further, there was no dose-response relationship observed with increasing number of ablations.
Highlights
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24 h-ambulatory blood pressure was reduced at 6 months after renal denervation.
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Response was not related to the presence of accessory renal arteries.
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Response was most pronounced in patients with small renal artery diameter (≤4 mm).
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No dose-response relationship was observed with increasing number of ablations.
1
Introduction
Catheter-based renal denervation (RDN) has been introduced to treat patients with uncontrolled hypertension [ , ]. Early uncontrolled and unblinded studies documented large changes in blood pressure (BP) [ ]. The controversially discussed randomized, sham-controlled Symplicity HTN-3 trial showed no significant difference in BP reduction between patients treated with RDN or sham [ ]. Until then, most trials only included patients with favorable renal artery anatomy, which was defined as (i) absence of accessory renal arteries or renal atherosclerotic disease including previous angioplasty or stenting, (ii) ≥4 mm in diameter and (iii) ≥20 mm in length of the main renal artery even though almost 50% of the hypertensive patients are considered anatomically ineligible for RDN according to these criteria [ ]. The randomized, sham-controlled SPYRAL HTN-OFF MED study provided biological proof of principle for the BP lowering efficacy of RDN in patients without an accompanying antihypertensive drug therapy [ ]. In the latter, anatomical eligibility criteria were less restrictive, as vessels with diameters from >3 mm to <8 mm and patients with accessory renal arteries were also considered treatable. It remains of utmost importance to identify patients with a high likelihood of future BP response to RDN. Therefore, this study investigated the association of anatomical and procedural determinants and their impact on 24 h-ambulatory BP (ABP) change.
2
Material and methods
A total of 150 hypertensive patients undergoing bilateral RDN were enrolled prospectively in this single-center trial between March 2009 and June 2013. Eligible patients were ≥18 years and had resistant hypertension according to the European Society of Hypertension/European Society of Cardiology guidelines (office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive drugs including a diuretic at maximum tolerated dose) [ ]. All patients provided written informed consent and were included in the Global Symplicity Registry [ ]. Local ethic committees approved the study. Participating patients underwent a complete medical history, physical examination, BP measurements and routine blood chemistry at baseline and at the subsequent follow-up after 6 months. The adherence to antihypertensive therapy was confirmed by direct questioning. Glomerular filtration rate (GFR) was assessed using cystatin C measurements. OBP were obtained with an automated oscillometric device (Omron HEM-705 monitor, Omron Healthcare, Vernon Hills, Illinois, USA) and were performed in concordance with the Joint National Committee VII Guidelines [ ]. 24 h-ambulatory blood pressure measurements (ABPM) were ascertained with an automated oscillometric device (Spacelabs 90207, Spacelabs Healthcare, Snoqualmie, Washington, USA) according to the latest European Society of Cardiology guidelines [ ]. Previous studies defined response to RDN as SBP reduction ≥10 mm Hg in OBP or ≥5 mm Hg 24 h-ABP after 6 months [ , ]. In the following, response to RDN is based on ABPM, unless otherwise specified.
2.1
Renal denervation and quantitative vascular analysis (QVA)
RDN was performed using the single-electrode radiofrequency (RF) Symplicity Flex catheter (Medtronic Vascular, Santa Rosa, California, USA). All procedures were performed by experienced interventionalists who had performed ≥10 renal interventions per year. The number of ablations and the treatment of accessory renal arteries were at the interventionalist’s discretion. Patients with hemodynamically significant renal artery stenosis diagnosed by non-invasive means were excluded in advance. Procedural data were recorded, and two experienced investigators blinded to patient’s characteristics assessed QVA using the CAAS II Research System (Pie Medical Imaging, Maastricht, Netherlands).
2.2
Anatomical parameters
Fig. 1 depicts the nomenclature applied herein. Morphometric parameters such as minimum, mean and maximum diameter as well as length were documented for the main renal arteries and in particular for the proximal (p), middle (m) and distal (d) segments as previously described [ ]. The division point in two or more consecutive branches of at least 3 mm in diameter defined the end of the main renal artery. Renal arteries other than the main renal artery were defined as accessory renal arteries. These could be of similar size and penetrating the hilus or smaller and supplying a minor part of the kidney. Accessory renal arteries were evaluated regarding mean diameter and length. For further comparisons and analysis, the largest caliber vessel of each side was determined. Renal artery disease included patients with hemodynamically non-significant renal artery stenosis (<50%) or prior renal artery interventions.
2.3
Statistical analysis
Data management and all statistical analysis were done with IBM SPSS Statistics (version 23.0; SPSS Inc., Chicago, Illinois, USA). Data are presented as the mean ± standard deviation (SD) or median and interquartile range (IQR) for continuous variables and as numbers (%) for categorical variables unless otherwise specified. Comparisons between groups were performed using Pearson’s χ 2 -test or Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test or the Kruskal-Wallis test for continuous variables where appropriate. A two-tailed p -value < 0.05 was defined to be statistically significant.
2
Material and methods
A total of 150 hypertensive patients undergoing bilateral RDN were enrolled prospectively in this single-center trial between March 2009 and June 2013. Eligible patients were ≥18 years and had resistant hypertension according to the European Society of Hypertension/European Society of Cardiology guidelines (office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive drugs including a diuretic at maximum tolerated dose) [ ]. All patients provided written informed consent and were included in the Global Symplicity Registry [ ]. Local ethic committees approved the study. Participating patients underwent a complete medical history, physical examination, BP measurements and routine blood chemistry at baseline and at the subsequent follow-up after 6 months. The adherence to antihypertensive therapy was confirmed by direct questioning. Glomerular filtration rate (GFR) was assessed using cystatin C measurements. OBP were obtained with an automated oscillometric device (Omron HEM-705 monitor, Omron Healthcare, Vernon Hills, Illinois, USA) and were performed in concordance with the Joint National Committee VII Guidelines [ ]. 24 h-ambulatory blood pressure measurements (ABPM) were ascertained with an automated oscillometric device (Spacelabs 90207, Spacelabs Healthcare, Snoqualmie, Washington, USA) according to the latest European Society of Cardiology guidelines [ ]. Previous studies defined response to RDN as SBP reduction ≥10 mm Hg in OBP or ≥5 mm Hg 24 h-ABP after 6 months [ , ]. In the following, response to RDN is based on ABPM, unless otherwise specified.
2.1
Renal denervation and quantitative vascular analysis (QVA)
RDN was performed using the single-electrode radiofrequency (RF) Symplicity Flex catheter (Medtronic Vascular, Santa Rosa, California, USA). All procedures were performed by experienced interventionalists who had performed ≥10 renal interventions per year. The number of ablations and the treatment of accessory renal arteries were at the interventionalist’s discretion. Patients with hemodynamically significant renal artery stenosis diagnosed by non-invasive means were excluded in advance. Procedural data were recorded, and two experienced investigators blinded to patient’s characteristics assessed QVA using the CAAS II Research System (Pie Medical Imaging, Maastricht, Netherlands).
2.2
Anatomical parameters
Fig. 1 depicts the nomenclature applied herein. Morphometric parameters such as minimum, mean and maximum diameter as well as length were documented for the main renal arteries and in particular for the proximal (p), middle (m) and distal (d) segments as previously described [ ]. The division point in two or more consecutive branches of at least 3 mm in diameter defined the end of the main renal artery. Renal arteries other than the main renal artery were defined as accessory renal arteries. These could be of similar size and penetrating the hilus or smaller and supplying a minor part of the kidney. Accessory renal arteries were evaluated regarding mean diameter and length. For further comparisons and analysis, the largest caliber vessel of each side was determined. Renal artery disease included patients with hemodynamically non-significant renal artery stenosis (<50%) or prior renal artery interventions.
2.3
Statistical analysis
Data management and all statistical analysis were done with IBM SPSS Statistics (version 23.0; SPSS Inc., Chicago, Illinois, USA). Data are presented as the mean ± standard deviation (SD) or median and interquartile range (IQR) for continuous variables and as numbers (%) for categorical variables unless otherwise specified. Comparisons between groups were performed using Pearson’s χ 2 -test or Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test or the Kruskal-Wallis test for continuous variables where appropriate. A two-tailed p -value < 0.05 was defined to be statistically significant.
3
Results
Baseline patient’s characteristics are depicted in Table 1 . Patients mean age was 63.8 ± 9.7 years, 58% were male with a mean body mass index (BMI) of 30.8 ± 5.2 kg/m 2 . Coronary artery disease (CAD) and type 2 diabetes were diagnosed in 36 (24%) and 61 (41%) patients, respectively. Despite an average of 5.4 ± 1.3 prescribed antihypertensive drugs, SBP and diastolic blood pressure (DBP) was 166 ± 22 mm Hg and 89 ± 16 mm Hg, respectively, with a mean heart rate of 67 ± 11 beats per minute (bpm).
| All patients | Responder | Non-responder | p Value # | |
|---|---|---|---|---|
| (n = 150) | (n = 91) | (n = 59) | ||
| Demographics | ||||
| Age, y | 63.8 ± 9.7 | 64.3 ± 9.8 | 63.0 ± 9.4 | 0.377 |
| Male gender | 87 (58%) | 51 (56%) | 36 (61%) | 0.547 |
| Body mass index, kg/m 2 | 30.8 ± 5.2 | 30.6 ± 5.5 | 31.1 ± 4.7 | 0.526 |
| Risk factors and target organ damage | ||||
| Type II diabetes mellitus | 61 (41%) | 34 (37%) | 27 (46%) | 0.306 |
| Coronary artery disease | 36 (24%) | 24 (26%) | 12 (20%) | 0.398 |
| Cystatin C GFR, mL/(min ∗ 1.73 m 2 ) | 77.5 ± 31.8 | 78.5 ± 33.1 | 76.0 ± 29.7 | 0.542 |
| Office blood pressure and heart rate measurements | ||||
| SBP, mm Hg | 166.3 ± 21.7 | 165.7 ± 21.9 | 167.1 ± 21.7 | 0.628 |
| DBP, mm Hg | 88.5 ± 15.5 | 88.2 ± 15.3 | 88.9 ± 16.1 | 0.763 |
| ISH a | 69 (46%) | 42 (46%) | 27 (46%) | 0.963 |
| Pulse pressure, mm Hg | 77.8 ± 20.1 | 77.5 ± 20.2 | 78.3 ± 20.1 | 0.788 |
| Office heart rate, bpm | 66.6 ± 10.8 | 66.8 ± 10.8 | 66.4 ± 11.0 | 0.896 |
| Antihypertensive treatment | ||||
| Number of antihypertensive drugs | 5.4 ± 1.3 | 5.5 ± 1.4 | 5.3 ± 1.1 | 0.704 |
| ACEi/ARB | 135 (90%) | 81 (89%) | 54 (92%) | 0.616 |
| Beta-blockers | 134 (89%) | 83 (91%) | 51 (86%) | 0.355 |
| Diuretics | 133 (89%) | 80 (88%) | 53 (90%) | 0.717 |
| Aldosterone antagonists | 31 (21%) | 12 (20%) | 19 (21%) | 0.936 |
| Calcium channel blockers | 112 (75%) | 69 (76%) | 43 (73%) | 0.686 |
| Central sympatholytics | 91 (61%) | 54 (59%) | 37 (63%) | 0.680 |
| Alpha-blockers | 40 (27%) | 27 (30%) | 13 (22%) | 0.302 |
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