Author + information
- Oliver Dörr, MD∗ (, )
- Christoph Liebetrau, MD,
- Helge Möllmann, MD,
- Luise Gaede, MD,
- Christian Troidl, PhD,
- Vanessa Haidner, MD,
- Jens Wiebe, MD,
- Sandra Voss, PhD,
- Timm Bauer, MD,
- Christian Hamm, MD and
- Holger Nef, MD
- ↵∗Department of Cardiology, University of Giessen, Klinikstrasse 33, Giessen 35392, Germany
The renal sympathetic denervation (RSD) is an interventional treatment option in resistant hypertension when optimal medical treatment fails, but this procedure has proved unsuccessful in some patients (1). Therefore, identifying patients who would potentially benefit from RSD remains a major clinical challenge. The sympathetic stimulation of the cardiovascular system is partly regulated by nerve growth factors and neurotrophic factors (2). Brain-derived neurotrophic factor (BDNF) is the most investigated member of the neurotrophin family and is an important modulator of the synaptic plasticity and activity of the sympathetic nervous system (2). Therefore, the primary aim of the present analysis was to evaluate whether BDNF would indicate successful denervation of the sympathetic nerve fibers and provide immediate assessment of a sufficient RSD procedure.
A total of 100 consecutive patients with resistant hypertension who underwent RSD were included in the study. Office and ambulatory blood pressure measurements (ABPMs) were obtained at baseline and 6 months after RSD. Office blood pressure (BP) was measured in each arm in the morning with patients in a sitting position after resting for at least 5 min. The arm with the higher BP was used for subsequent readings. Venous blood samples for determination of BDNF levels were collected at baseline and at 2 h and 6 months after RSD. A therapeutic response was defined as an office systolic BP (SBP) reduction of more than 10 mm Hg 6 months after RSD. The pre-procedural and follow-up management of these patients was recently published (3).
Six months after RSD, there was a significant reduction in the mean office SBP of 24.3 mm Hg (p < 0.001). Further, we observed a significant reduction in BDNF serum levels at 2 h after RSD (p < 0.001). Seventy-nine patients (79%) were classified as responders, with a mean office SBP reduction of more than 10 mm Hg 6 months after RSD. There were significant differences between BP responders and nonresponders regarding changes in BDNF levels 2 h after RSD. Correlation analysis revealed a significant relationship between baseline SBP values and RSD-related SBP reduction at the 6-month follow-up. In addition, there was a significant correlation between the decrease in BDNF serum levels 2 h after RSD and SBP reduction at the 6-month follow-up (p < 0.001).
Data from the recently published randomized, blinded HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial failed to meet its primary efficacy endpoint because the study did not show a significant reduction in SBP in patients with resistant hypertension 6 months after RSD compared with a sham control arm. Accordingly, based on the HTN-3 trial, there is leading evidence that suggests that RSD may not be superior to a placebo effect (4). These data contradict the results of several previous nonrandomized trials (1). Consequently, patient selection, operator experience, and technical aspects of the procedure have been considered as possible causes of these contrasting results (1,4).
The present study proposes for the first time an immediate assessment of the success of sympathetic nerve fiber denervation as reflected by BDNF as a specific biomarker. BDNF is a key mediator of neuronal and synaptic plasticity and regulates neurotransmitter production in the sympathetic nervous system; it is mainly associated with synaptic regulation in humans (2). Decreased BDNF expression contributes to an impaired density of sympathetic activity and transmitter release (3). Importantly, in the present study, we observed a significant decrease in BDNF levels immediately after RSD. Moreover, there was a significant correlation between the extent of an early decrease in BDNF level and SBP reduction at the 6-month follow-up (Table 1). These results suggest an association between RSD-related changes in BDNF levels and the degree of success of the RSD procedure, an assumption that is in line with the significant differences that we observed in the extent of early BDNF level changes between BP responders (p < 0.001) and nonresponders (p = 0.45) (Table 1).
In accordance with previous investigations, we observed a significant SBP reduction in office BP readings as well as in ABPMs at the 6-month follow-up (1,3,4). However, RSD-related changes in SBP were more pronounced in office BP measurements than in ABPMs. These observations may be partly explained by the statistical phenomenon of “regression to the mean,” which primarily affects office BP measurements and is also known from pharmacological trials.
In the present study, the immediate analysis of BDNF levels was restricted to 2 h after RSD. Additional, sequential BDNF analyses during the early post-procedural period may lead to further improvements and accordingly needs to be evaluated to appropriately implement the assessment of this biomarker in clinical practice.
To the best of our knowledge, this is the first study that provides a biomarker-based approach for an immediate assessment of the success of the RSD procedure. The acute BDNF level reduction was associated with SBP reduction after 6 months of follow-up. Moreover, the significant difference in BDNF level changes between BP responders and nonresponders additionally underlines this assumption.
Please note: Dr. Hamm is on the advisory board of Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation