Rami Tzafriri, Felix Mahfoud, Sahil A. Parikh, Elazer Edelman. “Quantification of Procedural and Anatomical Determinants of Multi-electrode Renal Denervation”
Background: The failure of the prospective, randomized, sham-controlled SYMPLICITY HTN-3 trial to show significant difference in reduction of systolic BP (SBP) in patients with resistant hypertension 6 months after RDN compared to controls was attributed in part to procedural limitations in first generation devices. The confirmation of BP lowering in 3 recent randomized, sham-controlled feasibility and proof of concept studies of multi-electrode RF and ultrasound RDN in patients with and without concomitant antihypertensive medication supports this interpretation. This is notable as our preclinical evaluation of radiofrequency RDN catheters predicted the clinical trends and high rates of variability.
Methods: Pigs were treated with 1-5 electrodes, sacrificed at 7d. Renal norepinephrine (NEPI) levels were measured and renal arteries processed for histology and morphometry. Findings were interpreted based on statistical and computational models that account for experimentally inferred nerve distribution and arterial microanatomy.
Results: Periarterial innervation is asymmetric and may limit the response to endovascular denervation. Histomorphometry and computational modeling illustrated that RF ablation patterns are sensitive to periarterial microanatomy, and particularly to presence of heat sinks. Treatments directed at large neighboring veins reduced ablation areas, and had suboptimal efficacy. NEPI levels exhibited a threshold dependence with the percentage of affected nerves across the range of treatment settings. Under uniform 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 annular geometry of the artery revealed that, regardless of settings, total ablation area and circumferential coverage were the prime determinants of RDN efficacy, with increased efficacy at smaller diameters.
Conclusions: The acceleration of regulatory evaluation of medical therapies obliges us to manage preclinical research to support robust translation of their innovation.
Presented at TCT 2019, September 25-29, San Francisco, CA.