Sahil A. Parikh

Endogenous Cell Seeding Remnant Endothelium After Stenting Enhances Vascular Repair

BACKGROUND Endothelial integrity is essential for maintaining vascular homeostasis, and endothelial denudation results in neointimal thickening. Balloon-expandable endovascular stents provide a luminal scaffolding within atherosclerotic arteries with minimal direct contact between balloon and endothelium. We wondered whether stents cause diminished endothelial ablation, and if so, whether the degree of endothelial damage might determine later proliferative sequelae. METHODS AND RESULTS Stainless steel stents were expanded in normal or previously denuded iliac arteries of New Zealand White rabbits. Stented arteries were harvested 15 minutes, 1 hour, 3 days, or 14 days later. En face staining of the luminal surfaces of stented arteries demonstrated that endothelial cell loss began immediately after stent expansion and was restricted to interstices between stent struts. Remnant endothelium adjacent to struts provided the foundation for complete endothelial regeneration of the stented segment within 3 days. Both early monocyte adhesion and later intimal macrophage accumulation were reduced > 80% in nonballooned but stented arteries, in concert with a twofold reduction in intimal thickening after 14 days, compared with arteries completely denuded with a balloon before stent expansion. CONCLUSIONS It is accepted that deep injury caused by balloon-expanded endovascular stents is a critical contributor to experimental stent-induced neointimal hyperplasia. Our data indicate that the degree of endothelial injury may also be an important component of vascular repair after stenting and an important consideration in stent and balloon design and use. The use of stents for primary endovascular intervention may allow partial retention of endothelium within treated arteries, thereby modulating vascular repair with less need for adjunctive pharmacological therapy.

Endothelial cell delivery for cardiovascular therapy.

Obstructive atherosclerotic vascular disease stands as one of the greatest public health threats in the world. While a number of therapies have been developed to combat vascular disease, endothelial cell delivery has emerged as a distinct therapeutic modality. In this article, we will review the anatomy of the normal blood vessel and the biology of the intact endothelium, focusing upon its centrality in vascular biology and control over the components of the vascular response to injury so as to understand better the motivation for a cell-based form of therapy. Our discussion of cell delivery for cardiovascular therapy will be divided into surgical and interventional approaches. We will briefly recount the development of artificial grafts for surgical vascular bypass before turning our attention towards endothelial cell seeded vascular grafts, in which endothelial cells effectively provide local delivery of endogenous endothelial secretory products to maintain prosthetic integrity after surgical implantation. New techniques in tissue and genetic engineering of vascular grafts and whole blood vessels will be presented. Methods for percutaneous interventions will be examined as well. We will evaluate results of endoluminal endothelial cell seeding for treatment of restenosis and gene therapy approaches to enhance endogenous re-endothelialization. Finally, we will examine some innovations in endothelial cell delivery that may lead to the development of endothelial cell implants as a novel therapy for controlling proliferative vascular arteriopathy.

SCAI expert consensus statement for renal artery stenting appropriate use.

The pathophysiology of atherosclerotic renal artery stenosis (RAS) includes activation of the renin‐angiotensin‐aldosterone axis with resultant renovascular hypertension. Renal artery stenting has emerged as the primary revascularization strategy in most patients with hemodynamically significant atherosclerotic RAS. Despite the frequency with which hemodynamically significant RAS is observed and high rates of technical success of renal artery stenting, there remains considerable debate among experts regarding the role of medical therapy versus revascularization for renovascular hypertension. Modern, prospective, multicenter registries continue to demonstrate improvement in systolic and diastolic blood pressure with excellent safety profiles in patients with RAS. Modern randomized, controlled clinical trials of optimal medical therapy versus renal stenting particularly designed to demonstrate preservation in renal function after renal artery stenting have demonstrated limited benefit. However, these trials frequently excluded patients that may benefit from renal artery stenting. This document was developed to guide physicians in the modern practical application of renal stenting, to highlight the current limitations in the peer‐reviewed literature, to suggest best‐practices in the performance of renal stenting and to identify opportunities to advance the field.

Critical role for Syk in responses to vascular injury

Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.

Endovascular therapy for acute ischaemic stroke: a systematic review and meta-analysis of randomized trials

AIMS Evidence from randomized controlled trials (RCTs) evaluating possible benefits of endovascular therapy (EVT) for acute ischaemic stroke has shown conflicting results. The purpose of this meta-analysis was to systematically examine clinical outcomes in RCTs comparing the use of intravenous (IV) fibrinolysis alone to IV fibrinolysis plus EVT, for the treatment of acute ischaemic stroke. METHODS AND RESULTS We selected English language RCTs, comparing EVT plus IV tissue-type plasminogen activator (tPA) (if eligible) with IV tPA alone in eligible patients for the treatment of acute ischaemic stroke. The primary endpoint was good functional outcome [modified Rankin Scale (mRS) of 0-2]. Other major endpoints of interest were all-cause mortality and symptomatic intracerebral haemorrhage (sICH). The meta-analysis included 8 RCTs that randomized 2423 patients with large-vessel, anterior-circulation stroke. EVT significantly improved the rate of functional independence (90-day mRS of 0-2) when compared with IV fibrinolysis [odds ratio (OR) 1.73, 95% confidence interval (CI) 1.18-2.53, number needed to treat (NNT) = 9.3]. The all-cause mortality was lower with EVT compared with the control group; however, the result did not reach statistical significance (OR 0.89, 95% CI 0.68-1.15). The rate of sICH was not higher with EVT (OR 1.07, 95% CI 0.73-1.56). Analyses from only the recent trials (reported in 2014-15) showed further benefit (OR of mRS 0-2: 2.42, 95% CI 1.91-3.08, NNT = 5) with similar safety results. CONCLUSION In centres with advanced systems of stroke care, EVT significantly improved functional outcomes (without compromising safety) in patients with acute ischaemic stroke due to anterior circulation, large artery occlusion, compared with standard therapy.

Modern Radiation Therapy and Cardiac Outcomes in Breast Cancer

PURPOSE Adjuvant radiation therapy, which has proven benefit against breast cancer, has historically been associated with an increased incidence of ischemic heart disease. Modern techniques have reduced this risk, but a detailed evaluation has not recently been conducted. The present study evaluated the effect of current radiation practices on ischemia-related cardiac events and procedures in a population-based study of older women with nonmetastatic breast cancer. METHODS AND MATERIALS A total of 29,102 patients diagnosed from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Medicare claims were used to identify the radiation therapy and cardiac outcomes. Competing risk models were used to assess the effect of radiation on these outcomes. RESULTS Patients with left-sided breast cancer had a small increase in their risk of percutaneous coronary intervention (PCI) after radiation therapy-the 10-year cumulative incidence for these patients was 5.5% (95% confidence interval [CI] 4.9%-6.2%) and 4.5% (95% CI 4.0%-5.0%) for right-sided patients. This risk was limited to women with previous cardiac disease. For patients who underwent PCI, those with left-sided breast cancer had a significantly increased risk of cardiac mortality with a subdistribution hazard ratio of 2.02 (95% CI 1.23-3.34). No other outcome, including cardiac mortality for the entire cohort, showed a significant relationship with tumor laterality. CONCLUSIONS For women with a history of cardiac disease, those with left-sided breast cancer who underwent radiation therapy had increased rates of PCI and a survival decrement if treated with PCI. The results of the present study could help cardiologists and radiation oncologists better stratify patients who need more aggressive cardioprotective techniques.

Proximal versus distal embolic protection for carotid artery stenting: a national cardiovascular data registry analysis.

OBJECTIVES The aim of this study was to compare the stroke/death rates between proximal embolic protection devices (P-EPDs) and distal filter embolic protection devices (F-EPDs) in elective carotid artery stenting (CAS). BACKGROUND P-EPDs have theoretical advantages that may make them superior to F-EPDs for stroke prevention during CAS. METHODS We examined 10,246 consecutive elective CAS procedures performed with embolic protection in the NCDR CARE registry between January 2009 and March 2013. We analyzed crude and propensity-matched rates of in-hospital combined death/stroke in patients treated with P-EPDs versus F-EPDs. Secondary analyses included 30-day adverse event rates and stroke rates by the involved cerebrovascular territory. RESULTS P-EPDs were used in 590 of 10,246 cases (5.8%). Patients treated with P-EPDs had higher rates of symptomatic lesion status (46.8% vs. 39.7%, p<0.001), atrial fibrillation/flutter (16.1% vs. 13.0%, p=0.03), and history of a neurological event (51.2% vs. 46.6%, p=0.03). In unadjusted and propensity-matched analyses, differences in in-hospital stroke/death between P-EPD and F-EPD cohorts were nonsignificant (1.5% vs. 2.4%, p=0.16 and 1.6% vs. 2.0%, p=0.56, respectively). For patients with available data (n=7,693, 75.1%), 30-day adverse events rates were similar for P-EPDs and F-EPDs before (2.5% vs. 4.2%, p=0.07) and after (2.7% vs. 4.0%, p=0.22) propensity matching. CONCLUSIONS Use of a P-EPD during CAS was associated with low rates of in-hospital stroke/death similar to those with an F-EPD in the first comparative effectiveness study of the devices. An adequately powered randomized trial comparing clinical outcomes between these devices is unlikely to be feasible.

The Current State of Stem Cell Therapy for Peripheral Artery Disease

Patients with advanced peripheral arterial disease may develop critical limb ischemia with rest pain, non-healing ulcerations, and eventually may require major amputation despite currently available revascularization technologies. Stem cell therapies hold promise as novel therapeutics to promote vasculogenesis and improve tissue perfusion in these patients. This article reviews the current state of stem cell therapy for patients with peripheral arterial disease, with a focus on the cell types that have been studied, barriers to clinical development, and development of new endpoints for clinical trials.

Do Postmarketing Surveillance Studies Represent Real-World Populations? A Comparison of Patient Characteristics and Outcomes After Carotid Artery Stenting

Background— To evaluate outcomes after carotid artery stenting in larger real-world populations, the Food and Drug Administration mandated that companies conduct postmarketing surveillance (PMS) studies of approved stent systems. Whether PMS studies are representative of carotid artery stenting in routine clinical practice has not been established. Methods and Results— Within the National Cardiovascular Database Registry–Carotid Artery Revascularization and Endarterectomy (NCDR CARE) Registry, we compared patient and procedural characteristics, in-hospital outcomes, and subsequent all-cause mortality after carotid artery stenting in PMS study participants and nonparticipants. We conducted both crude and propensity score–adjusted comparisons for all outcomes between groups. Compared with nonparticipants, participants in PMS studies had lower rates of symptomatic carotid artery disease within the preceding 6 months, prior stroke, and acute evolving stroke at baseline. The PMS study participants had lower unadjusted rates of combined in-hospital death, stroke, or myocardial infarction (2.3% versus 4.1%; P <0.001), driven by lower rates of stroke (1.7% versus 2.7%; P =0.005) and death (0.3% versus 1.4%; P <0.001). Differences in survival persisted after propensity score adjustment (odds ratio, 0.44; 95% confidence interval, 0.21 to 0.95; P =0.04 for in-hospital mortality; and hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.97; P =0.02 for 2-year mortality). Baseline differences in neurological history explained the largest proportion of the difference in outcomes between groups. Conclusions— Participants in PMS studies for carotid artery stenting have different clinical and procedural characteristics and lower mortality compared with nonparticipants. Extrapolating results from PMS studies of carotid artery stenting to larger real-world settings should be done only with great caution. # Clinical Perspective {#article-title-31}Background— To evaluate outcomes after carotid artery stenting in larger real-world populations, the Food and Drug Administration mandated that companies conduct postmarketing surveillance (PMS) studies of approved stent systems. Whether PMS studies are representative of carotid artery stenting in routine clinical practice has not been established. Methods and Results— Within the National Cardiovascular Database Registry–Carotid Artery Revascularization and Endarterectomy (NCDR CARE) Registry, we compared patient and procedural characteristics, in-hospital outcomes, and subsequent all-cause mortality after carotid artery stenting in PMS study participants and nonparticipants. We conducted both crude and propensity score–adjusted comparisons for all outcomes between groups. Compared with nonparticipants, participants in PMS studies had lower rates of symptomatic carotid artery disease within the preceding 6 months, prior stroke, and acute evolving stroke at baseline. The PMS study participants had lower unadjusted rates of combined in-hospital death, stroke, or myocardial infarction (2.3% versus 4.1%; P<0.001), driven by lower rates of stroke (1.7% versus 2.7%; P=0.005) and death (0.3% versus 1.4%; P<0.001). Differences in survival persisted after propensity score adjustment (odds ratio, 0.44; 95% confidence interval, 0.21 to 0.95; P=0.04 for in-hospital mortality; and hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.97; P=0.02 for 2-year mortality). Baseline differences in neurological history explained the largest proportion of the difference in outcomes between groups. Conclusions— Participants in PMS studies for carotid artery stenting have different clinical and procedural characteristics and lower mortality compared with nonparticipants. Extrapolating results from PMS studies of carotid artery stenting to larger real-world settings should be done only with great caution.

Imaging a spiral dissection of the superficial femoral artery in high resolution with optical coherence tomography—Seeing is believing

Optical coherence tomography (OCT) offers an alternative to intravascular ultrasound (IVUS) for endovascular imaging. Clinical and research applications for OCT have emerged in percutaneous coronary intervention (PCI), however, OCT has not found similar utility in peripheral arterial interventions. Early generation time‐domain OCT systems required arterial occlusion to create the blood free environment needed for image acquisition and could not reliably scan vessel diameters encountered in the peripheral circulation. However, the frequency‐domain OCT (FD‐OCT) system currently FDA approved for use in the United States does not require arterial occlusion to generate images and permits a greater scan diameter allowing for exploratory use in peripheral arteries. To our knowledge, this is the first report using non‐occlusive OCT imaging to serve as an adjunct to endovascular intervention for femoropopliteal disease. We illustrate the feasibility of acquiring high resolution images of a spiral dissection of the superficial femoral artery following balloon angioplasty that was not adequately visualized by angiography.