Vartan Ghazarossian

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.

Intravascular probe for detection of vulnerable plaque

Coronary angiography is unable to define the status of the atheroma, and only measures the luminal dimensions of the blood vessel, without providing information about plaque content. Up to 70% of heart attacks are caused by minimally obstructive vulnerable plaques, which are too small to be detected adequately by angiography. We have developed an intravascular imaging detector to identify vulnerable coronary artery plaques. The detector works by sensing beta or conversion electron radiotracer emissions from plaque-binding radiotracers. The device overcomes the technical constraints of size, sensitivity and conformance to the intravascular environment. The detector at the distal end of the catheter uses six 7mm long by 0.5mm diameter scintillation fibers coupled to 1.5m long plastic fibers. The fibers are offset from each other longitudinally by 6mm and arranged spirally around a guide wire in the catheter. At the proximal end of the catheter the optical fibers are coupled to an interface box with a snap on connector. The interface box contains a position sensitive photomultiplier tube (PSPMT) to decode the individual fibers. The whole detector assembly fits into an 8-French (2.7 mm in diameter) catheter. The PSPMT image is further decoded with software to give a linear image, the total instantaneous count rate and an audio output whose tone corresponds to the count rate. The device was tested with F-18 and Tl-204 sources. Spectrometric response, spatial resolution, sensitivity and beta to background ratio were measured. System resolution is 6 mm and the sensitivity is >500 cps / micrometers Ci when the source is 1 mm from the detector. The beta to background ratio was 11.2 for F-18 measured on a single fiber. The current device will lead to a system allowing imaging of labeled vulnerable plaque in coronary arteries. This type of signature is expected to enable targeted and cost effective therapies to prevent acute coronary artery diseases such as: unstable angina, acute myocardial infarction, and sudden cardiac death.

Performance of intravascular probe in animal studies

Up to 70% of heart attacks are thought to be caused by vulnerable plaque in arterial walls. We report on the first preclinical tests of an intravascular imaging detector to identify vulnerable coronary artery plaques. The detector identifies plaque by sensing beta emission from radiotracers, which bind to the vulnerable plaque. The detector design consists of a bundle of six 7 mm long scintillating fibers each fused to a 1.5 m plastic fiber. The scintillating fibers are offset from each other longitudinally by 6 mm and arranged spirally around a guide wire in the center of the catheter. To demonstrate the detection performance of this probe, excised arteries of transgenic mice were scanned using a single fiber version of the probe. The distal end of the probe was scanned over the arteries using a micrometer, and 2D images of the beta activity in the arteries were made. The images were later superimposed on autoradiographic images acquired from the same arteries to confirm the uptake in the plaque. The beta imaging probe was able to detect beta labeled plaque and a high degree of correlation with the autoradiography results validated the concept of using such a device to identify vulnerable plaque in-vivo. The future development of the detector will include additional in-vivo studies with animal models, and further development of the intravascular probe for improved sensitivity and miniaturization.

Multi-element linear array of silicon detectors for imaging beta emitting compounds in the coronary arteries

Coronary artery disease (CAD) is the leading cause of death in most developed countries. A large portion of CAD is caused by rupture of unstable plaque, which is not detectable by current diagnostic methods. By labeling the unstable plaque with beta emitting radioisotopes, it is possible to detect these plaques with a very narrow in situ detector system. Our intra-vascular detector system is an imaging device, consisting of several silicon detectors mounted on a flexible PC-board inside of a 1.6 mm diameter catheter. The catheter shields the detectors from outside light and enables the device to he guided to the coronary arteries during an angiography session. Each silicon detector consists of a linear array of 20 square pixels,with pixel dimensions of 0.45 mm /spl times/ 0.45 mm.

Detector identification through light separation for miniature imaging probe

Coronary artery disease (CAD) is the leading cause of death in most developed countries. A large portion of CAD is caused by rupture of unstable plaque, which is not detected by current diagnostic methods. By labeling the unstable plaque with beta emitting radioisotopes, it is possible to detect the plaques with a very narrow in situ detector system that is placed with a coronary angiography guidewire. Our current detection system uses fiber optics, with a single detector at the tip of each fiber, connected to a position-sensitive photomultiplier tube (PSPMT). The small diameter of the coronary artery limits our current system to six optical fibers. To increase the number of pixels, we are studying a multidetector concept for each fiber. By having multiple scintillating fibers coupled in series, with each scintillating fiber emitting a unique wavelength spectrum, the number of pixels can be doubled or tripled. The light is separated before reaching the PSPMT with a single diffraction grating. The PSPMT separates the detectors in one direction by fiber, and in the other direction by the spectral splitting of the different wavelengths of the scintillators.

Perivascular Renal Denervation (PVRDTM): Chemical Renal Denervation with Micro-Doses of Ethanol Using the PeregrineTM Renal Denervation Device

In the 1930s–1950s surgical renal sympathectomy was used to treat severe hypertension [1–3]. Despite a successful lowering of blood pressure (BP) observed with surgical denervation, this technique was abandoned due to a relatively high morbidity and mortality, and as a result of the development of more effective oral antihypertensive medications

Peregrine System™ Infusion Catheter for Perivascular Renal Denervation

Since the 1930s, it has been known that injury or ablation of the sympathetic nerves in or near the outer layers of the renal arteries can dramatically reduce high blood pressure. As far back as 1952, the use of alcohol (ethanol) has been reported for tissue ablation in animal experiments. Specifically, Berne [1] describes the use of “painting” alcohol on the outside of a dog’s renal artery to produce nerve damage, leading to denervation. Current technology to achieve renal denervation includes local heat-delivery using endovascular ablation catheters based on RF or ultrasound energy These devices include Symplicity (Medtronic, Dublin), EnligHTN (St. Jude Medical, St. Paul, MN), and Vessix system developed by Boston Scientific, Marlborough, MA. These devices are delivered into the renal artery in a procedure similar to an angioplasty or stent deployment in which a guiding catheter will facilitate the advancement of the ablation device into the renal arteries. A randomized, placebocontrolled clinical trial of Symplicity showed that this technique may not be consistently effective, as the depth of penetration of the RF-generated heat does not reach the deeper nerves, nor provide “circumferential” ablation, thus resulting in inadequate denervation [2]. The objective for the research that follows is to demonstrate that needle based ethanol injection into the perivascular space from a percutaneously inserted catheter can be safe and potentially effective in human use.