Rami Tzafriri. “Quantitative preclinical insights into procedural and anatomical determinants of multi-electrode renal denervation efficacy”

Summary: Radiofrequency renal denervation (RDN) is under investigation for treatment of hypertension with variable success. First generation systems used a single, monopolar radiofrequency (RF) electrode to sequentially ablate a series of angularly staggered locations along the endoluminal surface of the renal artery without inducing vascular luminal stenosis. Despite early successes, the prospective, randomized, sham-controlled trial failed to show significant difference in reduction of systolic blood pressure in patients with resistant hypertension 6 months after RDN compared to sham controls, throwing the field into confusion. Post-hoc analysis of the procedural data revealed that only a small fraction of arteries that received 6 single-electrode treatments showed evidence of fully circumferential, four quadrant, ablations. Thus, amongst reasons cited for this unexpected result was suboptimal procedural performance with incomplete nerve ablation, and all agree that further optimization of RDN systems is necessary.

Second generation systems employ multiple electrodes to simultaneously ablate multiple areas along the renal artery with controlled spacing. These systems range from mono-polar to bi-polar balloons, to multi-electrode basket-shaped or helical catheters. Given the differences in electrode geometries, their arrangement on the catheter, and the differential powering protocols, each of these devices is likely to provide a unique array of ablation patterns that differs from that of the single-electrode first generation device and at least in theory, offer greater control on ablation delivery. Three randomized, sham-controlled feasibility and proof of concept studies confirmed the BP lowering efficacy of multi-electrode RF and ultrasound RDN in patients with and without concomitant antihypertensive medication. The treatment effects in these trials however, were variable as blood pressure was not reduced in all patients. Thus, there is currently insufficient understanding of the correlation between efficacy and ablation patterns.

To address this need, we developed animal and computational models to characterize the target anatomy and characterize the dependence ablation biomarkers examine the dependence of on RDN treatment parameters and anatomical variables. These studiers revealed that renal artery innervation was asymmetric and may limit the response to endovascular denervation. Moreover, histomorphometry and computational modeling both illustrated that RF ablation patterns are sensitive to periarterial microanatomy, and particularly to the presence of heat sinks such as blood vessels and lymph nodes. In particular, treatments directed at large neighboring veins resulted in sub-average ablation areas, and therefore contributed suboptimally to efficacy. Renal norepinephrine (NEPI) levels exhibited a threshold dependence on the percentage of affected nerves across the range of treatment settings. Under uniform treatment settings, NEPI reduction and %affected nerves tracked with number of electrode treatments, confirming additive effects of helically staggered ablations at low numbers of treatments and a saturating effect at 5-10 treatments. A statistical model that accounts for measured nerve distribution patterns and the annular geometry of the artery revealed that, regardless of treatment variables, total ablation area and circumferential coverage were the prime determinants of RDN efficacy, with increased efficacy at smaller diameters.

Taken together, these data explain a large body of clinical and preclinical results and can be used to guide the development of future denervation therapies.

Presented at Biointerface 2019, in the Cardiovascular session, September 4-6, 2019, Park City, Utah.