Randomised, blinded and controlled comparative study of chemical and radiofrequency-based renal denervation in a porcine model.

AIMS: The blood pressure-lowering effect of percutaneous renal denervation (RDN) is controversial. The success of RDN may be device-dependent. We sought to compare the efficacy of RDN by chemical neurolysis using alcohol (Peregrine System Infusion Catheter; Ablative Solutions, Inc., Menlo Park, CA, USA) to RDN by radiofrequency (RF) ablation with the single-electrode RF catheter (Symplicity Flex; Medtronic, Minneapolis, MN, USA) in a porcine model. METHODS AND RESULTS: This was a prospective, randomised, blinded study. Pigs were assigned to undergo bilateral RF ablation or chemical neurolysis. Primary endpoints were ablation depth and renal tissue norepinephrine (NE) concentrations at three-month follow-up. Twelve pigs underwent RF ablation (n=4) or chemical neurolysis by infusion of 0.3 mL (n=4) or 0.6 mL (n=4) alcohol. Ninety days after RF ablation and chemical neurolysis with 0.3 mL and 0.6 mL of alcohol, mean maximal tissue injury depth was 3.9±1.2 mm, 6.6±1.7 mm and 8.2±2.2 mm, respectively (p<0.001 for either dose of alcohol vs. RF ablation). Compared with historical controls, median renal tissue NE concentration reductions were 66%, 78% and 83% after RF ablation and chemical neurolysis using 0.3 mL and 0.6 mL alcohol, respectively (p=0.107 for chemical neurolysis vs. RF ablation). Mean total ablation area was significantly greater in both (0.3 mL and 0.6 mL) alcohol groups (p=0.0001 for both) than the RF ablation group (30.8±13.7 mm2, 41.6±12.4 mm2 and 11.0±7.5 mm2, respectively). CONCLUSIONS: RDN is more effective using chemical neurolysis than single-electrode RF ablation. Our findings suggest that the efficacy of RDN may be device-dependent.

Transcatheter Alcohol-Mediated Perivascular Renal Denervation With the Peregrine System: First-in-Human Experience.

OBJECTIVES: This study evaluated the first clinical use of a new endovascular approach to renal denervation, using chemical neurolysis, via periadventitial infusion of dehydrated alcohol (ethanol) to perform "perivascular" renal artery sympathetic denervation. BACKGROUND: Renal denervation remains a promising technology for the treatment of hypertension and other disorders. METHODS: A novel 3-needle delivery device (Peregrine System Infusion Catheter, Ablative Solutions, Inc., Kalamazoo, Michigan) was introduced into the renal arteries of 18 subjects with refractory hypertension. Microdoses of alcohol were infused bilaterally via the 3 needles into to the adventitial space (0.30 ml/artery, 37 arteries). Renal artery angiography was performed at the time of the procedure and at 6 months (n = 16). The primary safety endpoints were complications associated with the catheter insertion and delivery of the neurolytic agent or any major vascular access complications. The secondary performance endpoint was a reduction in office-based systolic blood pressure at 6 months compared with baseline. RESULTS: Procedural success was achieved in 100% of subjects (N = 18) and arteries (N = 37). There were no study-related adverse clinical events at follow-up. One death of a subject was recorded but determined by the investigator and an independent medical monitor to be non-study related. There were no angiographic observations of renal artery stenosis, aneurysms, or other renal artery abnormalities at 6 months (32 renal arteries). Sixteen of the 18 subjects had a 6-month follow-up. The mean office systolic blood pressure decreased from 175 ± 17 mm Hg to 151 ± 26 mm Hg (-24 mm Hg). There was an average reduction of antihypertensive medications from 3.4 (baseline) to 2.0 per subject at 6 months. CONCLUSIONS: Chemical renal denervation using the infusion of very low doses of alcohol directly into the adventitial space appears to be feasible and safe. This approach may be a promising alternative approach to perform catheter-based renal denervation. These results need to be confirmed in larger scale clinical studies.

Next generation renal denervation: chemical "perivascular" renal denervation with alcohol using a novel drug infusion catheter.

BACKGROUND/PURPOSE: We update the pre-clinical and early clinical results using a novel endovascular approach, to perform chemical renal denervation, via peri-adventitial injection of micro-doses of dehydrated alcohol (ethanol-EtOH). METHODS/MATERIALS: A novel, three-needle delivery device (Peregrine™) was used to denervate the renal arteries of adult swine (n = 17) and in a first-in-man feasibility study (n = 18). In the pre-clinical testing EtOH was infused bilaterally with one infusion per renal artery into to the perivascular space, using EtOH doses of 0.3 ml/artery (n = 8), and 0.6 ml/artery (n = 9), and with saline sham control (0.4 ml/artery n = 3). Renal parenchymal norepinephrine (NE) concentration (performed blindly), and safety were the primary endpoints. Data from the first-in-man study (n = 18) to evaluate device performance, safety and peri-procedural pain are reported. RESULTS: In the pre-clinical testing renal function was unchanged at 3-month follow-up. Angiography at 90 days (n = 34 arteries) demonstrated normal appearing renal arteries, unchanged from baseline, and without stenosis or other abnormalities. The reductions in mean renal parenchymal NE reductions at 3 months were 68% and 88% at doses of 0.3 and 0.6 ml, respectively (p < 0.001 vs. controls). In the first-in-man study, there was 100% device success, no complications, a mean treatment time of 4.3 ± 3 minutes/artery, and minimal or no patient discomfort during treatment. Angiography at 6-months showed no evidence of renal artery stenosis, and evidence of a reduction of blood pressure from baseline. CONCLUSION: Perivascular RDN using micro-doses of alcohol is a promising alternative to energy-based systems to achieve dose-dependent, predictable, safe and essentially painless renal denervation. Further clinical evaluation is warranted. SUMMARY: (For annotated table of contents) This paper describes the preclinical results, in a porcine model, and the early first-in-man results, using the Peregrine™ chemical renal denervation catheter to perform renal sympathetic denervation using micro-doses of alcohol.

Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model.

AIMS: We report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation. METHODS AND RESULTS: A novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. EtOH was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using EtOH doses 0.15 ml/artery; n=3, 0.30 ml/artery; n=3, and 0.60 ml/artery; n=3, with saline injection as a sham control (0.4 ml/artery; n=3), and naive subjects (n=7) as a true negative control. The renal parenchymal norepinephrine (NE) concentration at two-week follow-up was the primary efficacy endpoint. The mean renal NE reduction was 54%, 78% and 88% at doses of 0.15 ml, 0.30 ml and 0.60 ml, respectively (p<0.0001 vs. controls). Histological examination revealed marked, and deep, circumferential renal nerve injury at depths of 2-8 mm from the intimal surface. There was no evidence of device-related or EtOH-induced injury to the intimal layers. In some samples at the higher EtOH doses, there was focal loss of smooth muscle cells in the outer media. Angiography at 45 days demonstrated normal appearing renal arteries with no detectable stenoses (n=8). CONCLUSIONS: Circumferential adventitial delivery of very low doses of EtOH may be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation. Further study is warranted.

Intravascular radiation detectors for the detection of vulnerable atheroma.

An intravascular catheter was developed to identify inflammation in coronary atheroma. Inflammation in atheroma is associated with large numbers of macrophages. These cells have increased metabolism, increased expression of chemotactic receptors, and a high frequency of apoptosis-associated phosphatidylserine expression. Each of these parameters can be identified in vivo using specific radiolabeled agents: metabolism can be identified with 18F fluorodeoxyglucose (FDG), receptor expression with 99mTc monocyte chemotactic peptide-1, and apoptosis with 99mTc annexin V. The locally increased concentration of these tracers is readily demonstrable in experimental lesions by ex vivo autoradiography; however, the small lesion size makes it difficult to identify atheroma in the coronaries with conventional imaging equipment. In contrast, with a radiation-sensitive catheter, optimized to sense charged particle rather than gamma or x-radiation, specific lesions could be identified and localized. Charged particle radiation is emitted as a byproduct of nearly all radioactive decay but is typically most abundant in radionuclides that decay by beta emission (either positrons or negatrons). Prototype catheters, using a plastic scintillator mated to an optical fiber, have been tested in the laboratory with the positron-emitting radiopharmaceutical 18FDG. The catheter had sufficient sensitivity to detect lesions concentrating nanocurie concentrations of 18FDG. Ex vivo experiments in apo-e-/- mice confirmed the ability of the catheter to detect 18FDG in aortic lesions. These feasibility studies demonstrate the sensitivity of a beta-sensitive catheter system. Additional mechanical refinements are needed to optimize the system in anticipation of in vivo animal studies.

Intravascular probe for detection of vulnerable plaque.

PURPOSE: Coronary angiography defines geometry of lumen of artery. However, perhaps 70% of heart attacks occur when minimally obstructive thin capped fibroatheroma rupture, causing thrombus and arterial occlusion. We have developed an intravascular imaging detector to identify vulnerable coronary artery plaque. PROCEDURE: Detector measures beta or conversion electron emissions from plaque-binding radiotracers. Detector assembly fits into a 2-mm diameter catheter and overcomes technical constraints of size, sensitivity, and conformance to intravascular environment. RESULTS: Device was tested by stepping test point sources past detector to verify function. System resolution is 6.7 mm and sensitivity is 400 cps/microCi one mm from detector. CONCLUSION: This prototype is a first step in imaging of labeled vulnerable plaque in coronary arteries. This type of system may assist in development of targeted and cost effective therapies to lower incidence of acute coronary artery diseases (CAD) such as unstable angina, acute myocardial infarction, and sudden cardiac death.