Aorticorenal Ganglia Pacing - A step forward in unblinding renal denervation procedures?

Catheter-based renal denervation has proven its blood pressure lowering effect in prospective, randomized, sham-controlled trials in patients with uncontrolled hypertension with and without concomitant antihypertensive medication (1–3) and in real world registries (4). These studies used radio-frequency and ultrasound catheter systems to affect the renal afferent and efferent nerves located in the adventitia of the renal arteries (5). Although the recent trials documented significant changes in ambulatory and office blood pressure following renal denervation when compared with sham treatment, the individual variability in treatment response was remarkable. Ambulatory blood pressure dropped by less than 5 mmHg in up to a third of patients and by >15 mmHg in another third. Whether this heterogeneity is related to suboptimal patient selection or inappropriate procedural performance remains incompletely understood (6). The lack of procedural metrics of successful ablation of renal sympathetic nerves is problematic. There is consensus that energy denervation cannot mature without unblinding the interventionalist by providing an intra-procedure guide to titrate therapies, individualize treatment plans, and optimize ablation.

In this issue of the Journal, Qian et al. (7) evaluated pacing of the aorticorenal ganglia as a potentially useful physiological procedural endpoint in a preclinical model. Using 3 groups of sheep, they assessed regional anatomy and histology of the aorticorenal ganglia (group A), measured the hemodynamic response to the stimulation of the left and right aorticorenal ganglia before and after unilateral radiofrequency ablation (group B) or microwave renal denervation (group C). The aorticorenal ganglia were localized by positioning the tip of a stimulation catheter at multiple sites above and below of the ipsilateral renal artery ostium. An increase in blood pressure in conjunction with ipsilateral renal vasoconstriction within 30 seconds of stimulation was regarded as successful aorticorenal ganglia pace capture.

Successful site localization and pacing was marked by an increase in mean arterial blood pressure by 22 mmHg without significant changes in heart rate, and ipsilateral renal vasoconstriction (8% reduction in caliber). Radiofrequency ablation of the aorticorenal ganglia resulted in variable but significant reduction in ipsilateral kidney norepinephrine content by 54%.

Understanding of the complex anatomy of the kidney and its innervation came into its own after renal transplantation became routine, and indeed as early as 1968 definitive autopsy studies defined the anatomy of the renal plexus and the aorticorenal area in 57 adult cadavers (8). The kidneys are innervated by the renal plexus which in close vicinity to the renal artery. The aorticorenal ganglia are located at the origin of the renal artery from the abdominal aorta (Figure 1). They partly fuse with the celiac ganglion, and thoracic splanchnic nerves have rami which terminate in the aorticorenal ganglia. The ganglia are also connected to the renal plexus, intermesenteric nerves, celiac and superior mesenteric plexuses, adrenal gland, and possibly with the testicular and ovarian plexuses. This anatomic description from over half a century ago nicely illustrates the complexity, and cross-talk of the renal and splanchnic innervation in humans, and the likelihood that if effects are seen in the kidney they should also be seen elsewhere.

Figure 1A.

Human anatomy. Yellow and green circles indicate right and left aorticorenal ganglion.

Although the idea of targeting through feedback is appealing enough for many to want it to work in humans, there are anatomic, procedural and even historical elements to this approach that we must consider before moving forward.

The complex anatomy described above would suggest that stimulation of the aorticorenal ganglia in humans, beside increasing blood pressure and causing renal vasoconstriction, modulates motility of the bowel and ureter and function of testicle and ovary. Such off-target effects were not addressed or presented by Qian et al. It is possible that the general anesthesia required in these animal experiments masked events which may very well emerge in humans under conscious sedation. Given the promise of renal denervation and the profound effects that a clinical trial with no or adverse effects can have, we are obliged to ensure that the aorticorenal ganglia pacing and ablation achieve selective renal sympathetic denervation without causing collateral damage or affecting various organ functions. Moreover, in sheep, the aorticorenal ganglia were located within 30–40 mm superior, and 10–15 mm lateral to the left and right renal artery ostium (7). Pacing successfully captured the right aorticorenal ganglia in 79% (through the inferior vena cava) and the left in 50% (through the aorta), respectively. The area of aorticorenal ganglia capture was quite discrete; a movement of >5 mm of the catheter tip frequently resulted in loss of pace-capture. The median time to localization of the aorticorenal ganglia (initial pace capture) using fluoroscopy was reasonable, only ~ 7 min per site, but more time was probably spent in cases in which the ganglia could not be located. Will this be the case in humans? The expected anatomic distortion, local calcification and vascular tortuosity in patients with hypertension and related comorbidities, including renal insufficiency, may prolong the time to definition of ganglia target site.

From a procedural perspective, there are other complexities that deserve attention. Aorticorenal ganglia pacing-directed denervation requires at least two arterial access sites (one for the renal denervation catheter and one for pacing of the left ganglion), and one venous access (for pacing of the right ganglion). It is known that complications arise with each vascular access in patients with hypertension. Finally, stimulation of renal nerves through the renal artery with subsequent blood pressure and heart rate rise has been suggested in the past as a test to establish that ablation was achieved, and to predict a favorable blood pressure response during follow-up (9,10). However, there is also concern that a hypertensive response alone, is nonspecific and may represent stimulation of afferent, sensory (pain) fibers (11). The concept of aorticorenal ganglia stimulation is unique in a way that it not only involves blood pressure alterations through afferent nerve capture but renal vasoconstriction, which should result from renal efferent nerve capture. Unlike stimulation of the renal artery, aorticorenal ganglia pacing may allow for simultaneous and longitudinal assessment of catheter-based renal denervation efficacy. It would indeed be most interesting to assess variances in response to aorticorenal ganglia pacing during application of different renal denervation techniques (main versus branch ablation) and technologies (radiofrequency, ultrasound and alcohol injection) and to correlate acute hemodynamic effects with future blood pressure changes.

Qian and coworkers should be congratulated for demonstrating the feasibility of aorticorenal ganglia stimulation in a large animal model, for enhancing our understanding of renal innervation physiology, and for potentially guiding renal denervation procedures. Aorticorenal ganglion pacing may indeed represent an interesting tool to ascertain successful renal denervation in the catheterization laboratory and is perhaps the tool we are looking for in guiding energy application to treat hypertension. Their work is a step forward in unblinding renal denervation procedures. Because of its potential value, further studies will be needed to refine the methods and assure effective translation to human testing and application.

Figure 1B.

Schematic drawing of the location of aorticorenal ganglia. Yellow and green circles indicate right and left aorticorenal ganglion.