Author + information
- Received July 25, 2013
- Revision received October 12, 2013
- Accepted October 15, 2013
- Published online February 1, 2014.
- Stefano F. Rimoldi, MD∗∗ (, )
- Niklaus Scheidegger, BSc∗,
- Urs Scherrer, MD∗,†,
- Stefan Farese, MD‡,
- Emrush Rexhaj, MD∗,
- Aris Moschovitis, MD∗,
- Stephan Windecker, MD∗,
- Bernhard Meier, MD∗ and
- Yves Allemann, MD∗∗ ()
- ∗Department of Cardiology, Bern University Hospital, Bern, Switzerland
- †Facultad de Ciencias, Departamento de Biología, Universidad de Tarapacá, Arica, Chile
- ‡Department of Nephrology, Bürgerspital Solothurn, Solothurn, Switzerland
- ↵∗Reprint requests and correspondence:
Dr. Stefano F. Rimoldi or Dr. Yves Allemann, Department of Cardiology, University Hospital Bern, Freiburgstrasse 4, CH-3010 Bern, Switzerland.
Objectives This study sought to determine the vascular anatomical eligibility for catheter-based renal artery denervation (RDN) in hypertensive patients.
Background Arterial hypertension is the leading cardiovascular risk factor for stroke and mortality globally. Despite substantial advances in drug-based treatment, many patients do not achieve target blood pressure levels. To improve the number of controlled patients, novel procedure- and device-based strategies have been developed. RDN is among the most promising novel techniques. However, there are few data on the vascular anatomical eligibility.
Methods We retrospectively analyzed 941 consecutive hypertensive patients undergoing coronary angiography and selective renal artery angiography between January 1, 2010, and May 31, 2012. Additional renal arteries were divided into 2 groups: hilar (accessory) and polar (aberrant) arteries. Anatomical eligibility for RDN was defined according to the current guidelines: absence of renal artery stenosis, renal artery diameter ≥4 mm, renal artery length ≥20 mm, and only 1 principal renal artery.
Results A total of 934 hypertensive patients were evaluable. The prevalence of renal artery stenosis was 10% (n = 90). Of the remaining 844 patients without renal artery stenosis, 727 (86%) had nonresistant hypertension and 117 (14%) had resistant hypertension; 62 (53%) of the resistant hypertensive and 381 (52%) of the nonresistant hypertensive patients were anatomically eligible for sympathetic RDN.
Conclusions The vascular anatomical eligibility criteria of the current guidelines are a major limiting factor for the utilization of RDN as a therapeutic option. Development of new devices and/or techniques may significantly increase the number of candidates for these promising therapeutic options.
Arterial hypertension is the major cardiovascular risk factor worldwide (1). Despite substantial advances in drug-based treatment, arterial hypertension therapy remains a major challenge. According to recent surveys in the United States and Europe, only 26% to 63% of patients achieve target blood pressure (BP) values (2). To improve the number of well-controlled patients, novel procedure- and device-based strategies have been developed (3–5), particularly renal artery denervation (RDN).
Exaggerated systemic sympathetic activity has been shown to be a major pathophysiological mechanism triggering the development, maintenance, and progression of arterial hypertension (6). Furthermore, recent preliminary studies suggest that RDN may also have favorable effects in other conditions associated with exaggerated sympathetic drive, such as obstructive sleep apnea syndrome, insulin resistance, and chronic renal or heart failure (7–9). Particularly, increased renal sympathetic activity has been shown to play an important role in the regulation of systemic BP (10). Consistent with this observation, surgical sympathectomy has been shown to significantly reduce BP in hypertensive patients (11). However, this procedure was accompanied by severe orthostatic hypotension and incontinence in some patients (12). To obviate these surgery-related complications, several minimally-invasive, catheter-based renal sympathetic denervation techniques have been developed in recent years (3,13). After placement of a catheter in the renal arteries, radiofrequency energy is applied endoluminally to induce thermal injury of the renal sympathetic fibers located in the adventitia of the renal arteries. To use this technique and to minimize the risk of complications (i.e., renal artery stenosis and dissection), several anatomical criteria of the renal arteries have to be fulfilled (Table 1). According to the guidelines (14,15), the diameter of the renal arteries should not be inferior to 4 mm, and the length before division should be ≥20 mm. Moreover, no renal artery stenosis (RAS) (≥30%) and no extrarenal artery should be present.
The SYMPLICITY (Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension) study and others (16–18) reported 10% to 37% ineligibility among screened patients, because the anatomical criteria were not met. However, these data were limited due to the selected patient populations and the lack of detailed anatomical data.
In the present study, we aimed to determine the anatomical eligibility for RDN in a large population of consecutive patients with arterial hypertension undergoing renal angiography.
Patient selection and definitions
We retrospectively analyzed 941 consecutive hypertensive patients undergoing coronary angiography and concomitant selective renal arteriography between January 1, 2010, and May 31, 2012. Seven patients were excluded from the analysis, as their images were not suitable for evaluation (Fig. 1).
The study was approved by the institutional ethics committee, and informed consent was obtained from all patients.
Imaging of the renal arteries was performed by the invasive cardiologist performing coronary arteriography in patients with a history of (treated) hypertension, known hypertensive heart disease as diagnosed by echocardiography, or persistently elevated BP (>140/90 mm Hg), provided there was no previous assessment of the renal arteries.
Resistant hypertension was defined according to the current guidelines (19). Coronary artery disease and peripheral artery disease were defined as previously described (20). Impaired renal function was defined by a glomerular filtration rate of <60 ml/min/1.73 m2, as estimated by the MDRD (Modification of Diet in Renal Disease) equations (21). Diagnosis of dyslipidemia and of diabetes mellitus were based on the 2013 European Society of Hypertension/European Society of Cardiology guidelines (19).
Significant RAS was defined as lumen narrowing ≥50% diameter, as previously described (20).
Selective and quantitative renal arteriography
Eight experienced staff cardiologists performed the 934 selective renal arteriographies considered in the study. The percutaneous femoral approach was used with standard 4- to 7-F Judkins or Amplatz catheters (Cordis, Miami Lakes, Florida). After coronary angiography, renal arteriography was performed by selectively injecting contrast medium into main and accessory renal arteries. All images were recorded digitally. The projection that best showed the anatomy was used for all analyses. Measurements were performed on cineangiograms. The contrast-filled, nontapered tip of the catheter was used for calibration. Digital angiograms were analyzed with the use of an automated edge-detection system (CAAS II, Pie Medical Imaging, Maastricht, the Netherlands), as previously described (22). Quantitative measurements included the diameter and length of the reference vessel. The intraobserver and interobserver variability of the quantitative measurements has been reported previously (23). The intraobserver (N.S.) and interobserver (N.S., S.F.R.) coefficients of variation for renal artery length were 1.3% and 2.8% and for renal artery diameter were 2.5% and 3.4%, respectively.
Extrarenal arteries were divided into 2 groups: hilar (accessory) and polar (aberrant) arteries (Fig. 2). Anatomical eligibility for catheter-based renal sympathetic denervation was defined according to previous studies and current guidelines (14–17): absence of renal artery stenosis, renal artery diameter ≥4 mm, renal artery length ≥20 mm, and only 1 main renal artery (Table 1).
Early division was defined as the presence of an additional renal artery departing at ≤20 mm from the orifice of the main renal artery.
Data were analyzed using GraphPad Prism version 5.0 (GraphPad Software Inc., La Jolla, California). Chi-square analysis was done for comparison of categorical data between groups. Data are expressed as mean ± SD. Statistical significance was defined at a p value of <0.05.
The study included 941 patients (Fig. 1) of whom 934 had good quality images. Patient characteristics are summarized in Table 2. The number and anatomy of the renal arteries in the study population is summarized in Table 3. A single renal artery was present in 731 patients (78%), and 197 patients (21%) had a double artery. Among them were 100 accessory (Fig. 2A) and 97 aberrant arteries (Fig. 2B). In 6 cases, 3 arteries vascularizing 1 kidney were present.
The prevalence of angiographically significant RAS was 7% (n = 65), and 25 patients (3%) had a nonsignificant RAS. Of the remaining 844 patients without RAS, 727 (86%) had nonresistant hypertension and 117 (14%) had resistant hypertension (Fig. 1). Based on the eligibility criteria (Table 1), 62 (53%) of the resistant hypertensive and 381 (52%) of the nonresistant hypertensive patients would have qualified for sympathetic RDN (Fig. 1, Table 4).
The most frequent reason for anatomical ineligibility (in 24% of nonresistant and in 28% of resistant hypertensive patients) was length of the main renal artery ≤20 mm (95% confidence limits: 3.6 to 18.2 mm in nonresistant and 3.0 to 17.9 mm in resistant hypertensive patients). In 19% of the patients, there was >1 main renal artery, and in 15% of patients, the diameter of the renal artery was <4 mm (95% confidence limits: 1.4 to 3.6 mm in nonresistant and 1.6 to 3.8 mm in resistant hypertensive patients) (Table 4).
The mean diameter of the left and right main renal arteries was 5.1 ± 1.0 and 5.1 ± 0.9 mm, respectively. The mean diameter of the accessory or aberrant arteries was 2.9 ± 0.8 mm on both sides (Table 3).
Catheter-based RDN is a novel, promising, minimally-invasive technique for the treatment of hypertension that was developed with the goal of achieving sustained BP reduction and control, particularly in patients with resistant hypertension. To be selected for RDN according to current recommendations (14,15), patients should satisfy several clinical criteria. Moreover, several anatomical characteristics of the renal arterial vascularization need to be fulfilled and play an important role in the selection process (Table 1). However, there are few detailed data on this issue. Previous studies just reported “global” rates of excluded patients owing to unfavorable vascular anatomical characteristics (16–18). Therefore, we studied in detail the anatomical characteristics of the renal arteries of almost 1,000 consecutive hypertensive patients undergoing coronary angiography and selective renal arteriography at our institution and applied the anatomical vascular inclusion and exclusion criteria used in previous RDN studies recommended by the current guidelines (14,15).
The main finding of this study was that anatomical vascular eligibility for RDN according to current recommendations (14,15) was met in 52% of patients with nonresistant and in 53% of patients with resistant hypertension. This figure is substantially lower than that reported in previous studies (16–18), with approximately 10% to 37% of the patients being excluded due to vascular anatomical criteria.
In the present study, the most common cause for anatomical ineligibility was an early division of the main renal artery both in nonresistant (24%) and resistant (28%) hypertensive patients. Previous studies on renal artery anatomy showed a prevalence of early division in the general population of 15% to 20% (24). The higher prevalence in our study may be related to the definition used for early division. According to the recommendations, we applied the criterion of a minimal length of 20 mm before branching, whereas previous studies used 15 mm. It may well be that several patients in the SYMPLICITY and other RDN trials (16–18) were included despite the fact that they did not strictly fulfill this (and other) anatomical criterion. This could, at least in part, explain the substantial difference between the number of actually excluded patients in these RDN trials and the number of patients not meeting the eligibility criteria on the basis of our renal vascular anatomy study.
The second most common cause for anatomical ineligibility in our study was the presence of additional renal arteries in 19% of the patients, a prevalence similar to what has been reported in previous anatomical studies (24–27). The pathophysiological role of accessory and/or aberrant renal arteries in the development or maintenance of (resistant) hypertension has not yet been adequately studied, and the results of small case series remain controversial: some suggest a possible role of aberrant renal arteries in the development of renin-dependent hypertension (28–30), whereas others suggest no relation between the presence of accessory renal arteries and hypertension (31). Not surprisingly, there is only anecdotal information on the role of accessory and/or aberrant renal arteries in the context of RDN, because its presence has been considered an exclusion criterion for the procedure (14,15). In 1 case report (32), successful single-sided RDN in a patient with a contralateral stenotic accessory renal artery was associated with significant improvement of arterial hypertension, suggesting that accessory renal arteries may play only a secondary role in the context of arterial hypertension and RDN.
The third most frequent reason for vascular ineligibility for RDN in our study was the presence of a main renal artery with a diameter <4 mm in 15% of the study participants, which is in accordance with results of previous anatomical studies (25–27). The development of new devices with the possibility to also perform RDN in smaller arteries (i.e., 3.0 mm) (13) is a promising technical improvement that will increase the number of eligible patients who may potentially benefit from this therapeutic approach.
First, this was a retrospective study, and the decision to perform renal angiography was at the discretion of the cardiologist who performed the coronary angiography but was made according to the pre-defined criteria as specified in the Methods section. Therefore, we cannot exclude that a selection bias occurred. However, we are confident that our results are reliable, as the percentage of patients fulfilling the anatomical eligibility criteria was similar in patients with resistant and nonresistant hypertension.
Second, use of local vasodilators during renal artery catheterization was not routinely performed. Hence, it is possible that some patients were inadequately excluded because of a vasoconstricted renal artery with a diameter <4 mm. However, in most denervation protocols, use of vasodilators prior to diameter measurement is not mandatory, and in the expert consensus statements (14,15), it is not part of the recommendations.
Finally, the absence of offline adjudication by a core laboratory is a potential weakness of the study. However, we are confident that our data are reliable, as both intraobserver and interobserver coefficients of variation for measurement of renal artery diameter and length were <3.5%.
The study shows that the strict application of the currently recommended anatomical vascular eligibility criteria for RDN would allow cardiologists to select only about 50% of hypertensive patients for this novel therapy, a major limiting factor. The data also suggest that the currently recommended anatomical criteria (14,15) were possibly not strictly applied for all the patients included in the recently reported clinical trials (16–18). Future studies assessing the effects of RDN in patients with accessory and/or aberrant arteries and the development of new devices and techniques allowing the use of RDN in patients not fulfilling the current anatomical vascular eligibility criteria may significantly increase the number of hypertensive patients who may take advantage of this novel therapeutic option.
Dr. Windecker has received research grants from Abbott Vascular, Cordis, Medtronic, Boston Scientific, Biotronik, Biosensors, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- blood pressure
- renal artery stenosis
- catheter-based renal artery denervation
- Received July 25, 2013.
- Revision received October 12, 2013.
- Accepted October 15, 2013.
- 2014 American College of Cardiology Foundation
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