Kenneth Rosenfield

Guidelines for the Early Management of Patients With Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Background and Purpose— The authors present an overview of the current evidence and management recommendations for evaluation and treatment of adults with acute ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators responsible for the care of acute ischemic stroke patients within the first 48 hours from stroke onset. These guidelines supersede the prior 2007 guidelines and 2009 updates. Methods— Members of the writing committee were appointed by the American Stroke Association Stroke Council’s Scientific Statement Oversight Committee, representing various areas of medical expertise. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Panel members were assigned topics relevant to their areas of expertise, reviewed the stroke literature with emphasis on publications since the prior guidelines, and drafted recommendations in accordance with the American Heart Association Stroke Council’s Level of Evidence grading algorithm. Results— The goal of these guidelines is to limit the morbidity and mortality associated with stroke. The guidelines support the overarching concept of stroke systems of care and detail aspects of stroke care from patient recognition; emergency medical services activation, transport, and triage; through the initial hours in the emergency department and stroke unit. The guideline discusses early stroke evaluation and general medical care, as well as ischemic stroke, specific interventions such as reperfusion strategies, and general physiological optimization for cerebral resuscitation. Conclusions— Because many of the recommendations are based on limited data, additional research on treatment of acute ischemic stroke remains urgently needed.

Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb

BACKGROUND Preclinical findings suggest that intra-arterial gene transfer of a plasmid which encodes for vascular endothelial growth factor (VEGF) can improve blood supply to the ischaemic limb. We have used the method in a patient. METHODS Our patient was the eighth in a dose-ranging series. She was aged 71 with an ischaemic right leg. We administered 2,000 micrograms human plasmid phVEGF165 that was applied to the hydrogel polymer coating of an angioplasty balloon. By inflating the balloon, plasmid DNA was transferred to the distal popliteal artery. FINDINGS Digital subtraction angiography 4 weeks after gene therapy showed an increase in collateral vessels at the knee, mid-tibial, and ankle levels, which persisted at a 12-week view. Intra-arterial doppler-flow studies showed increased resting and maximum flows (by 82% and 72%, respectively). Three spider angiomas developed on the right foot/ankle about a week after gene transfer; one lesion was excised and revealed proliferative endothelium, the other two regressed. The patient developed oedema in her right leg, which was treated successfully. INTERPRETATION Administration of endothelial cell mitogens promotes angiogenesis in patients with limb ischaemia.

Global experience in cervical carotid artery stent placement

The purpose of this article is to review and update the current status of carotid artery stent placement in the world. Surveys to major interventional centers in Europe, North and South America, and Asia were initially completed in June 1997. Subsequent information from these 24 centers in addition to 12 new centers has been obtained to update the information. The survey asked the various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 5,210 procedures involving 4,757 patients. There was a technical success of 98.4% with 5,129 carotid arteries treated. Complications that occurred during the carotid stent placement or within a 30‐day period following placement were recorded. Overall, there were 134 transient ischemic attacks (TIAs) for a rate of 2.82%. Based on the total patient population, there were 129 minor strokes with a rate of occurrence of 2.72%. The total number of major strokes was 71 for a rate of 1.49%. There were 41 deaths within a 30‐day postprocedure period resulting in a mortality rate of 0.86%. The combined minor and major strokes and procedure‐related death rate was 5.07%. Restenosis rates of carotid stenting have been 1.99% and 3.46% at 6 and 12 months, respectively. The rate of neurologic events after stent placement has been 1.42% at 6–12‐month follow‐up. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative for vascular surgery, especially for patients that are high risk for standard carotid endarterectomy. The periprocedure risks for major and minor strokes and death are generally acceptable at this early stage of development and have not changed significantly since the first survey results. Cathet. Cardiovasc. Intervent. 50:160–167, 2000. ©2000 Wiley–Liss,Inc.

ACC/AHA Guidelines for the Management of Patients with Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic)

A Collaborative Report from the American Associations for Vascular Surgery/Society for Vascular Surgery,* Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients with Peripheral Arterial Disease)—Summary of Recommendations

Current global status of carotid artery stent placement.

Our purpose was to review the current status of carotid artery stent placement throughout the world. Surveys were sent to major interventional centers in Europe, North and South America, and Asia. Information from peer-reviewed journals was also included and supplemented the survey. The survey asked various questions regarding the patients enrolled, procedure techniques, and results of carotid stenting, including complications and restenosis. Of the centers which were sent surveys, 24 responded. The total number of endovascular carotid stent procedures that have been performed worldwide to date included 2,048 cases, with a technical success of 98.6%. Complications that occurred during carotid stent placement or within a 30-day period following placement were recorded. Overall, there were 63 minor strokes, with a rate of occurrence of 3.08%. The total number of major strokes was 27, for a rate of 1.32%. There were 28 deaths within a 30-day postprocedure period, resulting in a mortality rate of 1.37%. Restenosis rates of carotid stenting have been 4.80% at 6 mo. Endovascular stent treatment of carotid artery atherosclerotic disease is growing as an alternative to vascular surgery, especially for patients that are at high risk for standard carotid endarterectomy. The periprocedural risks for major and minor strokes and death are generally acceptable at this early stage of development.

Histopathology of In-Stent Restenosis in Patients With Peripheral Artery Disease

BACKGROUND Clinical studies have suggested that smooth muscle cell (SMC) hyperplasia is the most likely cause of in-stent restenosis. However, pathological data regarding this issue are limited. Specifically, direct evidence of proliferative activity in tissues excised from stenotic stents has not been previously reported. METHODS AND RESULTS Tissue specimens were retrieved by directional atherectomy from 10 patients in whom in-stent restenosis complicated percutaneous revascularization of peripheral artery disease. Analysis of cellular composition was performed quantitatively after cell-specific immunostaining. For specimens preserved in methanol (7 of 10), cellular proliferation was evaluated by use of antibodies to proliferating cell nuclear antigen (PCNA), cyclin E, and cdk2. TUNEL staining for apoptosis was performed on 8 paraformaldehyde-preserved specimens. Each of the 10 specimens contained extensive foci of hypercellularity composed predominantly of SMCs (mean+/-SEM, 59.3+/-3.0%). Evidence of ongoing proliferative activity was documented in all 7 methanol-preserved specimens: 24.6+/-2.3% of SMCs were PCNA-positive, 24.8+/-3.1% were cyclin E-positive, and 22.5+/-2.2% were cdk2-positive. Apoptotic cells were detected in all 8 specimens that had been appropriately preserved to permit DNA nick-end labeling. Macrophages and leukocytes were identified in each of the 10 specimens but accounted for a proportionately smaller number of cells (14.5+/-1.9% and 9.5+/-1.4%, respectively). Organized thrombus was observed in 6 of the 10 specimens. CONCLUSIONS These findings support the notion that in-stent restenosis results from SMC hyperplasia and suggest that adjunctive therapies designed to inhibit SMC proliferation may further enhance the utility of endovascular stents.

Focal compensatory enlargement of human arteries in response to progressive atherosclerosis. In vivo documentation using intravascular ultrasound.

BACKGROUND Previous postmortem studies have demonstrated compensatory enlargement of atherosclerotic arteries in animal models and patients. Conclusions regarding these changes were drawn based on a comparison of the dimensions of diseased arteries in one group of subjects with the dimensions of normal arteries in another group. This method admits potential confounding variables, such as demographics and other disease states, which might also have an impact on arterial size. METHODS AND RESULTS Using intravascular ultrasound, we studied a total of 62 paired, adjacent normal and diseased sites in the superficial femoral arteries of 20 patients undergoing peripheral vascular interventions. Morphological assessment was performed using a computer-based image analysis system. Measurements were made of the cross-sectional area of the arterial lumen, the atherosclerotic plaque, and the outer border of the artery. These dimensions were then compared to determine the effects of progressive atherosclerosis on arterial morphology. Luminal cross-sectional area decreased from 21.1 +/- 2.2 mm2 in normal segments to 16.7 +/- 0.8 mm2 (P = .0001) in adjacent atherosclerotic segments. Similarly, minimal luminal diameter decreased from 5.7 +/- 0.2 to 5.0 +/- 0.1 mm2, and maximal luminal diameter decreased from 6.2 +/- 0.2 to 5.7 +/- 0.2 mm2. At these same sites, total arterial area was 32.9 +/- 1.6 and 37.9 +/- 1.9 mm2 (P = .0001) in normal and diseased segments, respectively. Minimal and maximal arterial diameters demonstrated similar increases (7.3 +/- 0.2 to 7.7 +/- 0.2 mm2 [P = .0015] and 7.6 +/- 0.2 to 8.3 +/- 0.2 mm2 [P = .0001], respectively). Regression analysis disclosed correlation of the cross-sectional area of plaque to the total arterial area (R = .70, P = .0001). CONCLUSIONS Human arteries enlarge in response to progressive atherosclerosis. This compensatory mechanism results in an increase in arterial size that is proportionate to the cross-sectional area of plaque that has accumulated in the vessel. Intravascular ultrasound demonstrates that this process is focal compensatory enlargement at discrete sites of atherosclerotic narrowing immediately adjacent to more normal areas in which arterial size is smaller.

Arterial Gene Therapy for Therapeutic Angiogenesis in Patients With Peripheral Artery Disease

### Peripheral Artery Disease: Primary Pharmacological Therapy Is Ineffective for Patients With Critical Limb Ischemia The prognosis for patients with chronic critical leg ischemia, ie, rest pain and/or established lesions that jeopardize the integrity of the lower limbs, is often poor. Psychological testing of such patients has typically disclosed quality-of-life indexes similar to those of patients with cancer in critical or even terminal phases of their illness.1 It has been estimated that in toto,2 150 000 patients per year require lower-limb amputations for ischemic disease in the United States. Their prognosis after amputation is even worse3 : the perioperative mortality for below-knee amputation in most series is 5% to 10% and for above-knee amputation 15% to 20%. Even when they survive, nearly 40% will have died within 2 years of their first major amputation; a major amputation is required in 30% of cases; and full mobility is achieved in only 50% of below-knee and 25% of above-knee amputees. These grim statistics are compounded by the lack of efficacious drug therapy. As concluded in the Consensus Document of the European Working Group on Critical Leg Ischemia,3 “. . .there presently is inadequate evidence from published studies to support the routine use of primary pharmacological treatment in patients with critical leg ischemia. . . .” Evidence for the utility of medical therapy in the treatment of claudication is no better.4 5 Consequently, the need for alternative treatment strategies in such patients is compelling. ### Therapeutic Angiogenesis Is a Novel Strategy for the Treatment of Critical Limb Ischemia The therapeutic implications of angiogenic growth factors were identified by the pioneering work of Folkman6 and other workers more than two decades ago. Beginning a little more than a decade ago,7 a series of polypeptide growth factors were purified, sequenced, and demonstrated to be responsible for natural as well as pathological angiogenesis. More recent investigations have established the feasibility of using recombinant formulations of such angiogenic growth …

Three-dimensional reconstruction of human coronary and peripheral arteries from images recorded during two-dimensional intravascular ultrasound examination

Background Intravascular ultrasound provides high-resolution images of vascular lumen, plaque, and subjacent structures in the vessel wall; current instrumentation, however, limits the operator to viewing a single, tomographic, two-dimensional image at any one time. Comparative analysis of serial two-dimensional images requires repeated review of the video playback recorded during the two-dimensional examination, followed by a “minds eye” type of imagined reconstruction. Methods and Results Computer-based, automated three-dimensional reconstruction was used to generate a tangible format with which to assess and compare a “stacked” series of two-dimensional images. Three-dimensional representations were prepared from sequential images obtained during intravascular ultrasound examination in 52 patients, 50 of whom were studied before and/or after percutaneous revascularization. Conventional two-dimensional ultrasound images were acquired by means of a systematic, timed pullback of the ultrasound catheter through the respective vascular segments. Images were then assembled in automated fashion to create a three-dimensional depiction of the vessel lumen and wall. Computer-enhanced three-dimensional reconstructions were generated in both sagittal and cylindrical formats. The sagittal format resulted in a longitudinal profile similar to that obtained during angiographic examination; in contrast to angiography, however, the. sagittal reconstruction offered 360° of limitless orthogonal views of the plaque and arterial wall as well as the vascular lumen. The cylindrical format yielded a composite view of a given vascular segment, and a hemisected version of the cylindrical reconstruction enabled en face inspection of the reconstructed luminal surface. Sagittal reconstructions facilitated analysis of dissections and plaque fractures resulting from percutaneous revascularization, and the hemisected cylindrical reconstructions enhanced analysis of endovascular prostheses. Conclusions This preliminary experience demonstrates that computer-based three-dimen-sional reconstruction may further augment the use of intravascular ultrasound in assessing vascular pathology and guiding interventional therapy.

Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease

BACKGROUND The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. METHODS In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention. RESULTS The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention. CONCLUSIONS Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541.).