Similar to the rising prevalence of obesity, in American adults the rate of uncontrolled hypertension (HTN) has risen from 15.9% (1988 to 1994) to 28.0% (2005 to 2008).1,2 As the socio-economic burden of the disease increases, there is significant enthusiasm for new innovative BP reduction therapies.
The key finding in HTN is an overactive sympathetic nervous system and the intimate role of the kidneys. Preclinical studies of non-selective thoracolumbar splanchicetomy to reduce the sympathetic drive was reported in the 1930’s. Renal denervation (RDN) therapy is an percutaneous targeted approach to ablate the renal nerves. SymplicityTM pioneered the radiofrequency based renal denervation system which demonstrated outstanding results in reducing systolic blood pressure in patients with resistant hypertension. There have been several key players that are emerging with both ultrasound and radiofrequency based electrodes for RDN, for which some analysts predict that the marketvalue for a blockbuster will hit $2 billion worldwide. While trans-arterial renal denervation has been the major focus of study, trans-ureteral renal denervation, non-invasive renal denervation, gamma knife and nanotechnology are some of the other ideas in the pipe-line focusing on the same target.
Extra-vascular Focused Ultrasonic Denervation KONA Technology
First-In-Man WAVE I clinical trials enrolled 24 patients with resistant hypertension. Results demonstrated an average of -29/12mmHg reduction in blood pressure at 24 weeks with an average therapy time of 12.6 minutes. There was renal artery stenosis, aneurysm , or pseudoaneurysm was observed at 6 months. Nine of the twenty-four patients reported muscular back discomfort beyond 72 hours, which resolved in 3 months with minimal analgesic use.
Results of Wave II clinical trial with 18 resistant hypertension patients demonstrated an average blood pressure reduction of -26/-9 at 24 week follow-up. Six patients reported muscular back pain beyond 72 hours which resolved by 3 months of minimal analagesic use. Three week MRI in all showed small areas of inflammation in peri-spinous muscles.
ApexNano is studying nanomagnetic particles for RDN where the particles are attached to Botox B as a neurotoxin and are injected into the renal artery and then pulled by an external magnetic field. Heat may be generated by modulation of the magnetic field releasing the neurotoxin andenhancing therenal nerve ablation. The work was catalyzed by Yu et al.3
Ablative Solutions procedure uses the PeregrineTM ablation catheter. This catheter has microneedles at the distal end which are advanced into the perivascular space of the renal artery. There ethanol is injected deep into the peri-adventitial space. First-in-man clinical testing in patients with resistant hypertension patients is planned for Q3 2013.
Novoste Beta Brachytherapy
BullFrog Micro-Infusion Catheter
renal denervation Mercator MedSystems
Historically, guanethidine had been used in the management of hypertension but was largely abandoned due to side effects [Moser, 2006]. Mercator Bullfrog Micro-Infusion system is the first guided-catheters to directly inject therapeutic guanentidine non-systemically through blood vessel walls into the deep tissues. The catheter has received CE Mark approval and FDA 510(k) clearance for the treatment of peripheral artery disease (PAD) and is now being studied for RDN procedures.4For RDN, the system is designed to inject guanethidine directly into the renal sympathetic nerve sheath using a guided 6-F compatible catheter.
The catheter is guided into the renal nerves where at the tip of the catheter the balloon is inflated and the microneedle slides through the vessel wall and up to 5mL/injection of guanethidineis inserted into the adventitia without any adverse events.4 Recently at the TREND 2013 meeting, preclinical data on animals who underwent RDN with injection of guanethidine showed reductions in norephinephrine levels.
Similar to the Bullfrog, the Northwind Technology platform is a 6-8F guide wire based catheter that injects small amounts of a neurotrophic agent into the renal artery walls, causing neuronal apoptosis. NW2013, the neurotrophic agent, binds to the ion pumps causing cytosolic Ca+ flux resulting in a cascade of reactions that ends in neuronal apoptosis. In preclinical studies, which were presented at TREND 2013, it was shown that NW2013 is more sensitive to neuronal nerves than guanethidine in rats. Dose-finding studies are in progress and first-in-human trials are planned for 2013-2014.
Baroreflex is one of the body’s homeostatic systems that provides a negative feedback loop in which an elevated blood pressure reflexively causes the heart rate to drop,reducing blood pressure. Similarly,a decrease in blood pressure activates the baroflex, causing the heart rate to increase thus increasing the blood pressure. Baroreceptor activation and increase in heart rate is due to sympathetic inhibition and parasympathetic activation.
An implantable device that electrically stimulates the carotid baroreceptors, thus inhibiting the sympathetic nervous system, is being studied in resistant hypertension patients. Clinical trials in patients with resistant hypertension with the implantable device showed significant reduction in both office systolic and diastolic blood pressurestudied. Further studies will need to be doneto determine this concept’s role in hypertension treatment.6
An interesting new renal denervation technology is CyberHeart, a propretiary software for ablation using stereotactic radiosurgery technology. Animal trials were completed with the system for renal denervation and data was presented at the American College of Cardiology meeting in 2013. Similar to ultrasound, energy is delivered non-invasively.
- Egan B.M., Zhao Y., Axon R.N., Brzezinski W.A., Ferdinand K.C.; Uncontrolled and apparent treatment resistant hypertension in the United States, 1988–2008. Circulation. 2011;124:1046-1058.
- Flegal K.M., Carroll M.D., Ogden C.L., Curtin L.R.; Prevalence and trends in obesity among US adults, 1999–2008. JAMA. 2010;303:235-241.
- Yu et al. Autonomic denervation with magnetic nanoparticles. Circulation. 2010;122: 2653-2659.
- Mercator Gains European Market Clearance for Advential Drug Delivery Catheters. Diagnostic and Interventional Cardiology. March 7, 2013.
- Rocha-Singh, K. Renal Artery Denervation: A Brave New Frontier Emerging therapies for treating patients with severe, treatment-resistant hypertension. Endovascular Today. 2012:Feb:45-52.
- Scheffers I, Schmidli J, Kroon AA, et al. Sustained blood pressure reduction by baroreflex hypertension therapy with a chronically implanted system: 2-year data from RheosDEBuT-HT study in patients with resistant hypertension. J Hypertension. 2008, 26(Suppl I): S19.