Renal Denervation: “ The end of the beginning” Professor Murray Esler at ACC

Professor Murray Esler delivered 45th Annual Louis F. Bishop Lecture at ACC.
Prof. Esler, pioneer of the landmark research that lead to our current understanding of the role of beta-blocker in the treatment of CHF, opened his talk with the question: “Is it the end of the beginning or the end of the end of renal denervation(RDN)? He is as sure as he was before January 9th, 2014 and convinced that the sympathetic nervous system (SNS) has a very important role to play in the pathogenesis of hypertension/ resistant HTN and that RDN has a role in treating patients suffering from this condition. Prof. Esler has been studying the sympathetic nervous system(SNS) for over 20 years and has developed an isotope method to study the role of SNS in circulatory control, exercise physiology, mental stress, obesity, congestive heart failure (CHF) and hypertension (HTN).

He kicked-off his presentation with a data review of the role of SNS in the pathogenesis of CHF, orthostatic intolerance, ventricular and atrial arrhythmia, and HTN. His opening slides consisted of Thomas Willis’s first ever drawing of the sympathetic nervous system from 1664 and moving forward to the work of Claude Bernard (1913, Surgical sympathectomy), William Paton (developed centrally acting anti-adrenergic drugs) he elaborated on the 4 decades of work from multiple continents showing renal denervation (including surgical denervation) inhibits the preferential activation of renal sympathetic outflow in drug resistant HTN. (Perhaps the commonly used drugs are not targeting the primary pathophysiology?) He briefly mentioned the regional norepinephrine spillover and selective reduction of the beta 1 receptor in the heart failure and Carvedilol trials showing the benefit of sympathetic inhibition on the mortality of heart failure patients.

His take on the Symplicity HTN-3: 
The mean reduction of SBP by14 mmHg in the RDN group and by 11.7 mmHg in the sham group is very likely from the execution of the study.

In the US, 88 centers enrolled 360 patients in the RDN arm and were treated by 140 interventionalist out of which 120 interventionalist performed only one procedure each in the trial and that is the only renal RF ablation procedure they have done in their career. “Mea culpa”

There was no marker to confirm that the denervation was achieved. In Symplicity I, 45% reduction in the renal vein norepinephrine spillover was measured in the 10 patients. In 70 pigs 85% reduction of NE renal spillover in the renal vein were noted. The effective ablation was less in those 10 patients than in the animal study. The human use of the Ardian Symplicity catheter is not easy and is usually incomplete. Reduction in NE spillover ranged in wide verity and proved it was operator dependent. Success of denervation is operator dependent. He further mentioned that another possibility is the inefficient first generation device: energy form, intensity and heat penetration. “HTN-3 will be judged to have failed to achieve adequate renal denervation and to be on the wrong side of history”. There are two trials where better BP control was achieved by repeating the procedure – “Or have better device to do first job better”.

When asked about the question of what he tells to the patients about the SYMPLICITY HTN-3 data he said: I tell my patient “You remember that special treatment for your HTN which fixed you up, a large overseas clinical trial showed that it did not work”.

For him, “The real science of renal denervation now begins”. Moving forward some of the current RDN mysteries will need to be solved:

How much RDN is optimal?
How to standardize the denervation?
How to test if denervation is achieved?
Pre-selection of patient”
Will RDN show a “class effect”?

Dr. Murray Esler closed with “It is End of the beginning and not the end of end.”