Innervation patterns may limit response to endovascular renal denervation

Abstract

Background: Renal denervation is a new interventional approach to treat hypertension with variable results.

Objectives: The purpose of this study was to correlate response to endovascular radiofrequency ablation of renal arteries with nerve and ganglia distributions. We examined how renal neural network anatomy affected treatment efficacy.

Methods: A multielectrode radiofrequency catheter (15 W/60 s) treated 8 renal arteries (group 1). Arteries and kidneys were harvested 7 days post-treatment. Renal norepinephrine (NEPI) levels were correlated with ablation zone geometries and neural injury. Nerve and ganglion distributions and sizes were quantified at discrete distances from the aorta and were compared with 16 control arteries (group 2).

Results: Nerve and ganglia distributions varied with distance from the aorta (p < 0.001). A total of 75% of nerves fell within a circumferential area of 9.3, 6.3, and 3.4 mm of the lumen and 0.3, 3.0, and 6.0 mm from the aorta. Efficacy (NEPI 37 ng/g) was observed in only 1 of 8 treated arteries where ablation involved all 4 quadrants, reached a depth of 9.1 mm, and affected 50% of nerves. In 7 treated arteries, NEPI levels remained at baseline values (620 to 991 ng/g), ≤20% of the nerves were affected, and the ablation areas were smaller (16.2 ± 10.9 mm(2)) and present in only 1 to 2 quadrants at maximal depths of 3.8 ± 2.7 mm.

Conclusions: Renal denervation procedures that do not account for asymmetries in renal periarterial nerve and ganglia distribution may miss targets and fall below the critical threshold for effect. This phenomenon is most acute in the ostium but holds throughout the renal artery, which requires further definition.

Keywords: aortic tortuosity; renal denervation; superior ostium.

FIGURE 1. Angiographic Confirmation of Electrode Positions Relative to the Ostium

Red arrows denote activated electrodes utilized for 2-electrode treatment (A) and 3-electrode treatment (B).

FIGURE 2. Histopathological Appearance of the Norepinephrine-Reducing Ostial Treatment

Treated renal artery sections (A) directly at or (C) ~3.0 mm away from the aorta with overlaid morphometry: ablation zone (black line), affected nerves (circled red), unaffected nerves (circled blue), and unaffected ganglion (circled green). Standardized comparison is facilitated by overlaying morphometric tracings from (A and C) onto nerve maps (B and D) with a defined, circular lumen (2.5 mm diameter). Orientation is uniform: top = ventral, left = cranial. In B and D, circle sizes denote the measured sizes of nerves (red = affected, blue = unaffected) and ganglia (green = unaffected). NEPI = norepinephrine; RA = renal artery; RDN = renal denervation; RF = radiofrequency.

FIGURE 3. Histopathological Appearance of Ostial Sympathetic Nerves

Magnified views of an unaffected nerve from Figure 2A (A) and an affected nerve from Figure 2C (B). Tyrosine hydroxylase immunostaining is strong and diffuse in the unaffected nerve (A) but patchy and granular in the affected nerve (B), which also exhibits hypercellularity and architectural disruption as part of the degenerative and proliferative response to treatment.

FIGURE 4. Nonefficacious Ostial Ablations

Maximal ablation zones along with nerve and ganglia positions and sizes at the same distance from the aorta (~0.3 mm) are depicted for treatments with norepinephrine levels as follows: 893 ng/g (A), 932 ng/g (B), and 620 ng/g (C). Circle sizes and other figure details as described in Figure 2.

FIGURE 5. Threshold to Biomarker Effect

Norepinephrine (NEPI) levels (diamonds) dependence on the percentage of affected nerves in affected arterial sections. A fit of Equation 1 (red line, R² = 0.85) estimates the threshold as 50.3% affected nerves.

FIGURE 6. The Radial Distributions of Nerves and Ganglia Become More Diffuse Closer to the Ostium

Histograms of the relative abundances of nerves and ganglia are depicted at ostial distances of 0.3 (A), 3.0 (B), and 6.0 mm (C). Data from Figures 7A to 7C.

FIGURE 7. Cross-Sectional Nerve and Ganglion Distributions Vary With Distance From the Aorta

Composite polar coordinate distributions are depicted at distances from the aorta: 0.3 (A), 3.0 (B), and 6.0 mm (C). Nerve and ganglia are depicted by closed circles of varying radii based on measured sizes. Red dashes depict the location of an idealized lumen. Purple dashes depict the locus of points that are 2.5 and 5.0 mm away from the lumen. Orientation: top = ventral, left = cranial.

CENTRAL ILLUSTRATION. Threshold to Biomarker Effect

Renal norepinephrine levels exhibit a threshold dependence on the percentage of affected nerves (blue circles), namely those residing within or at the periphery of the ablation zone (black line). Far from the ablation zones, nerves (blue circles) and ganglia (green circles) are unaffected.