Selective Proximal Renal Sympathetic Denervation Guided By Autonomic Responses Evoked Via High Frequency Stimulation In A Preclinical Canine Model

Background:With the aging of the population and rising rates of obesity, hypertension is increasing in prevalence worldwide. Approximately 10% of patients with diagnosed hypertension have drug-resistant hypertension, defined as a systolic blood pressure (BP) of 140 mmHg or higher despite adherence to at least three maximally tolerated does of antihypertensive medications from complementary classes, including a diuretic at an appropriate does. Such patients have high rates of cardiovascular complications, with few treatment options. Resistant hypertension has been linked to chronic excessive sympathetic drive, especially elevation of renal sympathetic activity in some groups of patients. Against this background, renal artery ablation selectively denervating the kidneys emerges as an alternative treatment for such patients. While initial trials showed promising results with regard to large reductions in BP, disappointingly, the potential therapeutic role of renal denervation (RDN) in lowering BP is being challenged after the failure of recent SYMPLICITY HTN-3 trial to show a benefit of RDN over the optimal medical therapy. For the time being, the BP-lowering effect of catheter-based renal denervation (RDN) is highly variable (the rates of non-response to RDN vary between 8-37%). Lacking of BP reductions following RDN may be the results of incomplete denervation.Objective:Electrical stimulation has been proved to be available to monitor the efficacy of RDN. In addition, recent studies indicated that renal sensory fibers converge on the proximal parts of renal arteries. Therefore, this study was to evaluate the effectiveness of high frequency stimulation (HFS) guided proximal RDN.Methods:A total of 24 healthy Chinese Kunming dogs were enrolled in the present study. Twelve animals were assigned to proximal RDN group (HFS+RDN, n=12) which underwent HFS and proximal renal artery ablation guided by the autonomic responses evoked via HFS. Another 12 animals were assigned to control group (HFS, n=12) which underwent HFS but no ablation on the proximal arteries was performed. After renal angiography screening, HFS (20Hz,8V, pulse width 2ms) was performed from proximal to distal renal artery in anatomically eligible dogs of both groups. Radiofrequency (RF) ablations were delivered in proximal RDN group and only at the proximal positive sites where systolic blood pressure (BP) increased>10mmHg during HFS. Post-ablation HFS was performed over the previously stimulated sites in proximal RDN group. BP, heart rate and plasma norepinephrine were analyzed.Results:After renal angiography screening,2 dogs in proximal RDN group and 4 dogs in control group were excluded and the remaining 18 dogs were anatomically eligible to perform HFS and RDN. Autonomic responses evoked by HFS were elicited in 13 of 18 (72.2%) dogs, including 8 of 10 (80%) dogs in proximal RDN group and 5 of 8 (62.5%) in control group. RF ablations were performed over HFS positive sites of proximal renal artery of 8 HFS responsive dogs in proximal RDN group. In 8 denervated dogs, pre-ablation HFS caused significant BP increases of 6.0±5.0/3.4±5.5 mmHg,16.9±11.7/11.1±8.5 mmHg, and 17.1±8.4/8.5±5.3 mmHg during the 1st,2nd, and 3rd 20 seconds of HFS at the proximal positive sites. Following ablation, these sites showed a negative response to post-ablation HFS with increases of BP by 1.3±3.0/1.0±2.5 mmHg,0.8±3.9/1.5±3.4 mmHg, and 1.5±4.5/0.7±3.8 mmHg. Of note, no RF applications were delivered at the positive sites of middle renal artery, repeated HFS increased BP only by 3.3±5.3/2,8±4.2 mmHg,5.3±6.6/3.8±4.7 mmHg, and 2.9±4.6/1.3±3.2 mmHg, failed to reproduce the previous BP increases of 6.2±5.6/5.3±4.4 mmHg,15.0±9.3/10.2±6.2 mmHg, and 14.9±7.7/8.4±4.7 mmHg. At 3 months, BP and plasma norepinephrine substantially decreased only in proximal RDN group (n=8). Whereas controls (n=5) showed minimal BP decreases and had similar plasma norepinephrine concentrations as baseline.Conclusion:Renal afferent nerves can be mapped safely and HFS guided targeted proximal RDN can achieve apparent BP reduction and sympathetic inhibition.