Safety and feasibility of a novel transcervical access neuroprotection system for carotid artery stenting in the PROOF Study.

BACKGROUND: Randomized controlled trials have shown that periprocedural rates of stroke and death are higher with carotid artery stenting (CAS) than with carotid endarterectomy (CEA) in the treatment of carotid artery stenosis. Diffusion-weighted magnetic resonance imaging (DW-MRI) has shown higher rates of clinically silent new ischemic brain lesions when CAS is performed as compared with CEA. The Silk Road Medical Embolic PROtectiOn System: First-In-Man (PROOF) Study is a single-arm first-in-man study using the MICHI Neuroprotection System (Silk Road Medical Inc, Sunnyvale, Calif), a novel transcervical access and cerebral embolic protection system. This system enables stent implantation under controlled blood flow reversal of the carotid artery, also known as Flow Altered Short Transcervical Carotid Artery Stenting (FAST-CAS). METHODS: Between March 2009 and February 2010, a total of 44 subjects were enrolled into the study. The primary composite endpoint was major stroke, myocardial infarction, or death within 30 days. Forty-three patients (97.7%) completed the study through the 30-day endpoint. One patient was lost to follow-up. In a subgroup of consecutive subjects, DW-MRI examinations were performed preprocedure and within 24 to 48 hours after the stent implantation. Blinded independent neuroradiologists reviewed all DW-MRI studies and confirmed the absence or presence of new ischemic brain lesions. RESULTS: All enrolled patients were successfully treated, and no major adverse events were seen through the follow-up period. Thirty-one subjects had DW-MRI examinations. Of these, five patients (16%) had evidence of new ischemic brain lesions but no clinical sequelae. Transient intolerance to reverse flow was reported in 9% of cases, but in all cases, a stent was successfully placed, and the intolerance was managed by minimizing the duration of reverse flow during the procedure. CONCLUSION: In this first-in-man experience, FAST-CAS using the MICHI Neuroprotection System was shown to be a safe and feasible method for carotid revascularization. DW-MRI findings suggest controlled reverse flow provides cerebral embolic protection similar to that seen with CEA.

Phase I drug and light dose-escalation trial of motexafin lutetium and far red light activation (phototherapy) in subjects with coronary artery disease undergoing percutaneous coronary intervention and stent deployment: procedural and long-term results.

BACKGROUND: Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment. METHODS AND RESULTS: An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy. CONCLUSIONS: This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.

StarClose femoral arteriotomy closure device: an advance in arterial closure.

Millions of femoral arterial punctures are performed annually worldwide for the diagnosis and treatment of cardiovascular disease. Traditionally, hemostasis following arterial sheath removal has employed compression techniques but more recently, a number of arteriotomy closure devices have become available, none of which have been shown to produce an outcome superior to the standard technique of compression. The authors investigated a novel device, which utilizes a nitinol clip that gathers the artery from the outside producing a purse-string-like seal, with very promising results. The authors feel that this device has great potential, may impact significantly on the closure of arteriotomy sites and may also find application in other aspects of procedural medicine.

Effects of enhanced external counterpulsation on Health-Related Quality of Life continue 12 months after treatment: a substudy of the Multicenter Study of Enhanced External Counterpulsation.

BACKGROUND: The Multicenter Study of Enhanced External Counterpulsation (MUST-EECP) was the first prospective, randomized, blinded, sham-controlled study of enhanced external counterpulsation (EECP) in the treatment of chronic stable angina. We previously reported that EECP therapy lengthens the time to exercise-induced myocardial ischemia and reduces angina. We now describe the effects of EECP therapy versus a sham-treated control group in terms of patients' functioning, their senses of well-being and other Health-Related Quality Of Life (HQOL) parameters from baseline to end of treatment and from baseline to 12 months after treatment. OBJECTIVE: To determine whether a 35-hour course of EECP affects the HQOL of patients with symptomatic coronary artery disease, 12 months following treatment. METHODS: Seventy-one of the 139 patients enrolled in MUST-EECP provided evaluable patient-completed questionnaires at baseline, at the end of treatment, and 12 months post-treatment. The Medical Outcomes Study 36-Item Short-Form Health Survey and the Quality of Life Index-Cardiac Version III were used to assess effects on HQOL. RESULTS: Both groups had similar HQOL scores at baseline. At end of treatment and at 12-month follow up, patients who had active-CP reported greater improvement than those who had inactive-CP in all nine quality of life scales, including ability to perform activities of daily living, ability to work, bodily pain, confidence in health, energy, ability to engage in social activities with family and friends, anxiety and depression, and quality of life issues from the effects of angina on health and functioning. Despite small sample sizes, active-CP patients demonstrated significantly greater improvement at 12 months following treatment in bodily pain, social functioning, and quality of life specific to cardiac patients compared with inactive-CP patients. CONCLUSION: Significant health-related quality of life improvements were measurable up to 12 months after the completion of treatment with EECP. Improvements in this controlled study are consistent with HQOL changes reported in case series and patient registries. Larger studies are warranted.

Pretreatment with intragraft verapamil prior to percutaneous coronary intervention of saphenous vein graft lesions: results of the randomized, controlled vasodilator prevention on no-reflow (VAPOR) trial.

BACKGROUND: Intragraft verapamil is effective in treating no-reflow during saphenous vein graft (SVG) percutaneous coronary intervention (PCI). In this study, we assessed the use of intragraft verapamil given pre-PCI to prevent no-reflow. METHODS: Patients undergoing SVG PCI were randomized to receive intragraft 200 g verapamil or no verapamil immediately prior to PCI. Pre- and post-PCI, vessel flow was assessed using TIMI flow grade and TIMI frame count by blinded angiographic readers. Tissue level perfusion in the graft territory was assessed using the TIMI myocardial perfusion grade (TMPG). CK-MB or troponin I levels were measured 6 12 hours post-PCI. RESULTS: Ten patients were randomized to the verapamil group and 12 were assigned to the placebo group. No-reflow occurred in 33.3% of the placebo group, compared to none of the verapamil patients (p = 0.10). The use of intragraft verapamil prior to SVG PCI increased flow rate in the vessel as assessed by TIMI frame count (53.3 22.4% faster in the verapamil group versus 11.5 38.9% in the placebo group; p = 0.016). There was a trend toward improved myocardial perfusion as assessed by TMPG. There was no difference in the incidence of cardiac biomarker release following PCI. CONCLUSIONS: Intragraft administration of verapamil prior to saphenous vein graft PCI reduces no-reflow and is associated with a trend toward improved myocardial perfusion.

Effect of intracoronary estradiol on postischemic microvascular damage in a porcine model: a myocardial contrast echocardiographic study.

Coronary microvascular damage can occur in the presence of myocardial ischemia even if epicardial vessels are patent, a phenomenon known as "no-reflow." Estrogens have favorable effects on coronary conductance and resistance arteries, and may have therapeutic value in ischemic syndromes. Myocardial contrast echocardiography (MCE) is a promising method for evaluating microvascular damage. In this study, the authors hypothesized that acute intracoronary 17beta-estradiol administration can reduce postischemic microvascular damage, which is evaluated by MCE, in a porcine model. Sixteen male pigs were randomized into 2 groups: the treatment group (n = 9) received intracoronary estradiol in increasing doses, and the control group (n = 7) received intracoronary vehicle (dimethylsulfoxide, DMSO). Microvascular damage was induced by balloon catheter occlusion followed by reperfusion of the left circumflex coronary artery (LCX). MCE using Levovist with harmonic imaging was performed before and during 15-minute balloon occlusion of the proximal LCX to determine perfusion areas of the left anterior descending artery (LAD) and LCX. MCE was performed immediately postocclusion and after each injection of estradiol (1, 10, and 100 nmol/L) or DMSO. Videodensitometry measurements were performed as a quantitative marker for myocardial microvascular damage. Videodensitometry results were expressed as peak intensity ratios. Intracoronary estradiol induced a significant reduction in myocardial microvascular damage after ischemic episode by videodensitometry measurements when compared to intracoronary DMSO. The authors conclude that intracoronary injection of estradiol reduces postischemic microvascular damage measured by MCE in a porcine model.

Initial experience with a new femoral artery closure device following percutaneous coronary intervention with glycoprotein IIb/IIIa inhibition.

The aim of the study was to determine the safety and efficacy of a novel femoral artery closure device (StarClose, Abbott Vascular Devices, Redwood City, CA) following percutaneous coronary intervention employing aspirin, heparin, and glycoprotein (GP) IIb/IIIa inhibition. A prospective nonrandomized single-center pilot study of the StarClose device included a subset of patients undergoing percutaneous coronary intervention utilizing GP IIb/IIIa inhibitors. Those that fulfilled the inclusion criteria (age < 80, no periprocedural haematoma, puncture above the superficial femoral and profunda femoralis artery bifurcation, no significant femoral artery disease) underwent closure of the femoral artery puncture site with a StarClose device immediately on completion of the procedure. Time to hemostasis (TTH), bleeding, mobilization, and short-term clinical follow-up data were collected, and an ultrasound scan of the femoral artery was performed 2 weeks later. Twenty-five patients were recruited, of whom 23 underwent percutaneous coronary intervention (PCI). Their mean age was 58 +/- 12 years, 84% were male, and 63% had unstable angina. All were on aspirin 100-150 mg daily and all PCI patients received i.v. heparin 4-10,000 units at commencement of the procedure and clopidogrel 600 mg on completion. Two patients were on a tirofiban infusion and 23 received a double bolus of eptifibatide, each 0.18 mg/kg, separated by 10 min. The procedural success was 100% and device success 23/25 (92%), with 1 failure due to technical error. The median device delivery time was 36 sec (range, 11-178) and median TTH 37 sec (range, 10-509 sec). There were no major adverse events. In 10 patients, a moderate amount of tract ooze required a short period of adjunctive manual compression. Follow-up ultrasound femoral artery scans revealed no compromise of the vessel lumen. Femoral artery closure with the device following coronary angiography and intervention using glycoprotein IIb/IIIa receptor inhibitors is safe and effective. A randomized trial of a larger number of patients is warranted.

Dehydroepiandrosterone sulfate induces acute vasodilation of porcine coronary arteries in vitro and in vivo.

Although an inverse relationship between dehydroepiandrosterone sulfate (DHEAS) and coronary artery disease has been demonstrated in men, the vascular effects of DHEAS are not well defined. The vasoactive effects of intracoronary DHEAS and testosterone (0.1 nM to 1 microM) were examined in vivo in 24 pigs. Epicardial cross-sectional area was measured by intravascular ultrasound, and coronary flow velocity by intravascular Doppler velocimetry. We also examined the effects of antagonism of the androgen receptor, nitric oxide synthase, and potassium channels on DHEAS-induced vasodilation in vitro in coronary rings from male and female pig hearts. DHEAS and testosterone induced increases in cross-sectional area, average peak velocity, and coronary blood flow. The maximal increase in coronary blood flow in response to testosterone was 1.26-fold (P=0.02), and in average peak velocity 1.43-fold (P=0.05), greater than that to DHEAS, whereas increases in cross-sectional area were similar. Vasodilation to both hormones was rapid, with maximal responses occurring <10 minutes after administration. In vitro, DHEAS and testosterone induced vasodilation in coronary rings, greater with testosterone. At doses of 0.1 and 1 microM, the vasodilator effects of DHEAS and testosterone were inhibited by the androgen receptor antagonist flutamide but not the estrogen receptor antagonist ICI 182,780. At 10 microM, neither DHEAS- nor testosterone-induced vasorelaxation was inhibited by flutamide, ICI 182,780, L-NAME, or deendothelialization, but both were attenuated by pretreatment with glibenclamide. No gender differences were observed in any of the responses examined. In conclusion, DHEAS is an acute coronary artery vasodilator, but less potent than testosterone. Its effect might be mediated via androgen receptors and may involve ATP-sensitive potassium channels.

Photodynamic therapy: applications in atherosclerotic vascular disease with motexafin lutetium.

Photodynamic therapy (PDT) has been approved as a tissue-specific light-activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues selectively is especially appealing for atherosclerotic plaque. Biotechnology has developed a new generation of selective photosensitizers and catheter-based technological advances in light delivery have allowed the introduction of PDT into the vasculature. The largest experience to date is with motexafin lutetium (MLu, Antrin), an expanded porphyrin (texaphyrin) that accumulates in plaque. The combination of the motexafin lutetium and endovascular illumination, or Antrin phototherapy, has been shown to reduce plaque in animal models. Antrin phototherapy generates cytotoxic singlet oxygen that has been shown to induce apoptosis in macrophages and smooth muscle cells. The safety, tolerability, and preliminary efficacy of Antrin phototherapy has been assessed in a phase 1 dose-ranging clinical trial in subjects with peripheral artery disease and is currently being examined in a phase 1 study in subjects with lesions of the native coronary arteries undergoing stent implantation. The preliminary results suggest that Antrin phototherapy is safe, well tolerated, and nontraumatic.