David R. Fischell

Inhibition of Neointimal Proliferation With Low-Dose Irradiation From a β-Particle–Emitting Stent

BACKGROUNDnRestenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a beta-particle-emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries.nnnMETHODS AND RESULTSnFourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven beta-particle-emitting radioisotope stents (32P, activity level 0.14 microCi) and seven control stents (31P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76 +/- 0.37 mm2 versus 2.81 +/- 1.22 mm2, P = .05) and percent area stenosis (24.6 +/- 2.9% versus 36.0 +/- 10.7%, P = .02) within the beta-particle-emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26 +/- 0.04 mm versus 0.38 +/- 0.10 mm, P = .012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the beta-particle-emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index.nnnCONCLUSIONSnA local, continuous source of low-dose endovascular irradiation via a beta-particle-emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.

Low-dose, beta-particle emission from 'stent' wire results in complete, localized inhibition of smooth muscle cell proliferation.

BACKGROUNDnRestenosis after catheter-based revascularization has been demonstrated to be primarily caused by medial and/or intimal smooth muscle cell (SMC) proliferation. The objective of this study was investigate the ability of local emission of beta-particles from a 32P-impregnated titanium stent wire source to inhibit vascular SMC and endothelial cell proliferation in cell culture and to determine the dose-response characteristics of this inhibition.nnnMETHODS AND RESULTSnA series of experiments were performed using 0.20-mm-diameter titanium wires that were impregnated with varying low concentrations of 32P (activity range, 0.002 to 0.06 microCi/cm wire, n = 47) or 31P (nonradioactive control, n = 28) in cultures of rat and human aortic SMCs and in cultured bovine aortic endothelial cells. The zone of complete cell growth inhibition (in millimeters from stent wire) was measured using light microscopy in the cultures exposed to the radioactive (32P) or control (31P) wires at 6 and 12 days after plating. In both rat and human SMC cultures there was a distinct 5.5- to 10.6-mm zone of complete SMC inhibition at wire activity levels > or = 0.006 microCi/cm. In contrast, there was no zone of inhibition surrounding the control (31P impregnated) wires (P < .001 versus 32P wires at all wire activities > or = 0.006 microCi/cm for human and rat SMCs). Proliferating bovine endothelial cells were more radioresistant than SMCs, with no zone of inhibition observed at wire activity levels up to 0.019 microCi/cm (P < .001 versus SMCs at 0.006 microCi/cm and 0.019 microCi/cm).nnnCONCLUSIONSnWe conclude that very low doses of beta-particle emission from a 32P-impregnated stent wire (activity levels as low as 0.006 microCi/cm of wire) completely inhibit the growth and migration of both rat and human SMCs within a range of 5.5 to 10.6 mm from the wire. Endothelial cells appear to be much more radioresistant than SMCs. These data suggest that an intra-arterial stent impregnated with a low concentration of 32P may have a salutary effect on the restenosis process. Whether this approach can be used successfully and safely to inhibit restenosis in vivo and in the clinical setting is under investigation.

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

AIMSnWe report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation.nnnMETHODS AND RESULTSnA 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).nnnCONCLUSIONSnCircumferential 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.

Initial Clinical Results Using Intracardiac Electrogram Monitoring to Detect and Alert Patients During Coronary Plaque Rupture and Ischemia

OBJECTIVESnWe report the first clinical studies of intracardiac ST-segment monitoring in ambulatory humans to alert them to significant ST-segment shifts associated with thrombotic occlusion.nnnBACKGROUNDnDespite improvements in door-to-balloon times, delays in symptom-to-door times of 2 to 3 h remain. Early alerting of the presence of acute myocardial infarction could prompt patients to seek immediate medical evaluation.nnnMETHODSnIntracardiac monitoring was performed in 37 patients at high risk for acute coronary syndromes. The implanted monitor continuously evaluated the patients ST segments sensed from a conventional pacemaker right ventricle apical lead, and alerted patients to detected ischemic events.nnnRESULTSnDuring follow-up (median 1.52 years, range 126 to 974 days), 4 patients had ST-segment changes of ≥3 SDs of their normal daily range, in the absence of an elevated heart rate. This in combination with immediate hospital monitoring led to angiogram and/or intravascular ultrasonography, which confirmed thrombotic coronary occlusion/ruptured plaque. The median alarm-to-door time was 19.5 min (6, 18, 21, and 60 min, respectively). Alerting for demand-related ischemia at elevated heart rates, reflective of flow-limiting coronary obstructions, occurred in 4 patients. There were 2 false-positive ischemia alarms related to arrhythmias, and 1 alarm due to a programming error that did not prompt cardiac catheterization.nnnCONCLUSIONSnShifts exceeding 3 SD from a patients daily intracardiac ST-segment range may be a sensitive/specific marker for thrombotic coronary occlusion. Patient alerting was associated with a median alert-to-door time of 19.5 min for patients at high risk of recurrent coronary syndromes who typically present with 2- to 3-h delays.

Next generation renal denervation: chemical “perivascular” renal denervation with alcohol using a novel drug infusion catheter

BACKGROUND/PURPOSEnWe 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).nnnMETHODS/MATERIALSnA 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.nnnRESULTSnIn 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.nnnCONCLUSIONnPerivascular 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.nnnSUMMARYn(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.

The Guardian: an implantable system for chronic ambulatory monitoring of acute myocardial infarction

The AngelMed Guardian is an implantable medical device that records cardiac data and detects ischemic events using a standard pacemaker intracardiac lead positioned in the right ventricular apex. The Guardian has been implanted in 55 people in the United States and Brazil and is currently undergoing a Food and Drug Administration phase 2 pivotal trial in the United States. The Guardian detects acute ischemic events by analyzing ST-segment shifts. The ST-segment shifts are calculated as the difference between the ST deviation of a current 10-second electrogram window and a baseline ST deviation value. If the ST-segment shift is greater than a heart rate-dependent programmable threshold, then the device generates an emergency alert signal. Results thus far have demonstrated that (i) the intracardiac electrogram is relatively noise-free and (ii) the ST-shift technique used by the Guardian is effective for detecting acute ischemic events.

Rationale and design of the AngeLmed for Early Recognition and Treatment of STEMI trial: A randomized, prospective clinical investigation

Significant improvements in door-to-balloon times have led to a reduction in mortality in ST-segment elevation myocardial infarction; however, mean symptom-to-door times remain at 2 to 3 hours. An intracardiac electrogram monitoring device may be beneficial in high-risk patients by alerting them to rapidly progressive ST-segment changes indicative of acute coronary occlusion. The Cardiosaver and DETECT phase I clinical studies demonstrated the safety, feasibility, and potential benefit of using an intracardiac electrogram monitoring device to alert the patient to seek medical attention. The goal of the randomized, prospective ALERTS Trial (Clinicaltrials.gov no. NCT00781118) is to evaluate the efficacy of an implantable monitoring device (IMD) in reducing the composite of either cardiac or unexplained death, new Q-wave myocardial infarction, or symptom-to-door time of >2 hours for confirmed thrombotic events. The IMD alerts the patient in real time when ST-segment deviation from a personalized baseline exceeds the trigger threshold. The trial is designed to enroll high-risk post-acute coronary syndrome patients or patients with previous multivessel coronary artery bypass surgery. All patients have the IMD implanted, with 1:1 unblinded randomization to the alerting feature being either turned on versus turned off for the first 6 months. Randomization occurs at the first follow-up visit, 7 to 14 days after the implantation of the IMD. Subjects then return for follow-up visits at months 1, 3, and 6 and thereafter every 6 months until closure of the investigational device exemption. Subjects who cannot be implanted successfully or who have the device explanted are removed from the study and followed up for a minimum of 30 days post-procedure. If a subject experiences a device-related complication and/or adverse experience, the subject is followed up until resolution or until the condition becomes stable and no further change is anticipated.

773-3 Inhibition of Neointimal Proliferation with a Beta Particle Emitting Stent

Neointimal proliferation in response to arterial injury is an important contributor to restenosis. Ionizing radiation inhibits cellular proliferation and may reduce neointimal formation following balloon angioplasty. Using a novel method to deliver a local endovascular radiation dose, we studied the effect of beta irradiation on the intimal proliferative response to placement of titanium stents in porcine iliac arteries. Fourteen titanium stents containing a true beta particle emitting radioisotope, 32p, were expanded in the iliac arteries of nine NIH miniature swine. Seven control stents, (no 32p), and seven treatment stents with an activity of 0.14 μCi, were deployed. Treatment effect was assessed by angiography and histomorphologic examination of the stented iliac segments at day 28. The cell proliferation index (%PCNA positive cells/HPF) and cell density (number of cells/HPF) were measured. Stent Type Intimal Area (mm2) Lumen Area (mm2) Percent Area Stenosis Control (nxa0=xa07) 2.47xa0±xa01.00 472xa0±xa00.67 33.5xa0±xa09.2% Treatment(nxa0=xa07) 1.77xa0±xa00.44 * 5.38xa0±xa00.81 * 24.6xa0±xa04.4% † * pxa0≤xa00.012 vs. control. † pxa0=xa00.0004 vs control Mean neointimal thickness at each wire site for the treatment stents was significantly less than for the control stents, (0.26xa0±xa0.05xa0mm vs, 0.34xa0±xa00.1 0xa0mm, pxa0=xa00.0037). The mean cell proliferation index (2.15:xa0±xa00.91% vs. 3.95xa0±xa04.21% pxa0=xa00.44) and cell density (362xa0±xa042 vs. 349xa0±xa045 pxa0=xa00.46) were similar between treatment and control stents. Conclusions Low dose endovascular irradiation by a beta particle emitting tent reduces neointimal proliferation after experimental stent placement. This novel technique offers potential for the prevention of restenosis.

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.