Renu Virmani

CVPath Institute, GAI, Maryland, United States

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Publications (63)376.92 Total impact

  • Kazuyuki Yahagi · Michael Joner · Renu Virmani
    Coronary artery disease 09/2015; 26(6):466-468. DOI:10.1097/MCA.0000000000000274 · 1.30 Impact Factor
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    ABSTRACT: Despite the reduction in late thrombotic events with newer-generation drug-eluting stents (DES), late stent failure remains a concern following stent placement. In-stent neoatherosclerosis has emerged as an important contributing factor to late vascular complications including very late stent thrombosis and late in-stent restenosis. Histologically, neoatherosclerosis is characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without necrotic core formation and/or calcification. The development of neoatherosclerosis may occur in months to years following stent placement, whereas atherosclerosis in native coronary arteries develops over decades. Pathologic and clinical imaging studies have demonstrated that neoatherosclerosis occurs more frequently and at an earlier time point in DES when compared with bare metal stents, and increases with time in both types of implant. Early development of neoatherosclerosis has been identified not only in first-generation DES but also in second-generation DES. The mechanisms underlying the rapid development of neoatherosclerosis remain unknown; however, either absence or abnormal endothelial functional integrity following stent implantation may contribute to this process. In-stent plaque rupture likely accounts for most thrombotic events associated with neoatherosclerosis, while it may also be a substrate of in-stent restenosis as thrombosis may occur either symptomatically or asymptomatically. Intravascular optical coherence tomography is capable of detecting neoatherosclerosis; however, the shortcomings of this modality must be recognized. Future studies should assess the impact of iterations in stent technology and risk factor modification on disease progression. Similarly, refinements in imaging techniques are also warranted that will permit more reliable detection of neoatherosclerosis.
    European Heart Journal 05/2015; DOI:10.1093/eurheartj/ehv205 · 14.72 Impact Factor
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    ABSTRACT: Background Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease. Methods and Results A systematic analysis was performed on 114 well‐characterized perirenal aortic specimens with immunostaining for T‐cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non‐Th1/Th17 ratio (CD4+T‐bet+/CD4+T‐bet−/CD4+/interleukin‐17+ double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B‐cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T‐cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions. This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T‐cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process. Conclusions Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a “critical” change in the inflammatory footprint before and during plaque destabilization.
    Journal of the American Heart Association 03/2015; 4(4):1403. DOI:10.1161/JAHA.114.001403 · 2.88 Impact Factor
  • T Koppara · R Virmani · M Joner
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    ABSTRACT: Drug--eluting stents are currently used in the majority of percutaneous coronary interventions. Preclinical investigations and human autopsy studies have shown that the high efficacy of drug-eluting stents in preventing restenosis is achieved at the expense of a delay in healing. Optical coherence tomography (OCT) represents a novel intracoronary imaging tool to evaluate vascular healing response after stent implantation. Owing to its outstanding resolution in the catheter near--field, quantitative morphometric measures were complemented by more qualitative description of neointimal tissue characterization. Clinical imaging studies employing these methodologies gained valuable insights into vascular healing responses after DES implantation and are reported in this review. However, an important limitation of OCT imaging analysis, despite its high resolution, remains the inability to assess the precise cellular composition and functional capability of the neointimal tissue, especially of the endothelium. Future long-term clinical studies are warranted to determine the clinical relevance of surrogate parameters derived from preliminary OCT surveillance studies.
    Minerva cardioangiologica 01/2015; 63(1). · 0.48 Impact Factor
  • R Zarpak · O. D. Sanchez · M Joner · L G Guy · G Leclerc · R Virmani
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    ABSTRACT: Current generations of monotherapy drug eluting stents only inhibit neointimal hyperplasia. However, these stent designs have other drawbacks such as delayed arterial healing, hypersensitivity, late stent thrombosis, and neoatherosclerosis, creating a need for a new generation of safer devices. The novel 'pro--healing' COMBOTM dual therapy stent aims to address these issues by reducing neointimal hyperplasia via an abluminal bioabsorbable polymer eluting sirolimus, and by simultaneously capturing circulating endothelial progenitor cells via luminally immobilized anti--CD34+ antibodies. Short--term pre--clinical data shows promising results as compared to 1st generation and 2nd generation drug eluting stents; however long--term literature remains unavailable until now. This review aims to evaluate, histopathologically, drawbacks of the current era of stents at autopsy, review short--term pre--clinical and clinical data from the REMEDEE trial, and present original long--term pre--clinical data. To date, pre--clinical data shows good performance of the COMBOTM stent comparable with the safety profile of bare metal stents with minimal inflammation, increased endothelialization, and acceptable neointimal hyperplasia with no statistical evidence of late catch up. Clinical data from the REMEDEE trial at 12 months shows non--inferiority to paclitaxel drug eluting stents, no evidence of late stent thrombosis, and a low rate of adverse clinical events.
    Minerva cardioangiologica 11/2014; 63(1). · 0.48 Impact Factor
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    ABSTRACT: Blood vessels are exposed to multiple mechanical forces that are exerted on the vessel wall (radial, circumferential and longitudinal forces) or on the endothelial surface (shear stress). The stresses and strains experienced by arteries influence the initiation of atherosclerotic lesions, which develop at regions of arteries that are exposed to complex blood flow. In addition, plaque progression and eventually plaque rupture is influenced by a complex interaction between biological and mechanical factors-mechanical forces regulate the cellular and molecular composition of plaques and, conversely, the composition of plaques determines their ability to withstand mechanical load. A deeper understanding of these interactions is essential for designing new therapeutic strategies to prevent lesion development and promote plaque stabilization. Moreover, integrating clinical imaging techniques with finite element modelling techniques allows for detailed examination of local morphological and biomechanical characteristics of atherosclerotic lesions that may be of help in prediction of future events. In this ESC Position Paper on biomechanical factors in atherosclerosis, we summarize the current 'state of the art' on the interface between mechanical forces and atherosclerotic plaque biology and identify potential clinical applications and key questions for future research.
    European Heart Journal 09/2014; 35(43). DOI:10.1093/eurheartj/ehu353 · 14.72 Impact Factor
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    ABSTRACT: Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drug-eluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis.
    The Journal of cardiovascular surgery 06/2014; 55(3):307-23. · 1.37 Impact Factor
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    ABSTRACT: Veins grafted into an arterial environment undergo a complex vascular remodeling process. Pathologic vascular remodeling often results in stenosed or occluded conduit grafts. Understanding this complex process is important for improving the outcome of patients with coronary and peripheral artery disease undergoing surgical revascularization. Using in vivo murine cell lineage-tracing models, we show that endothelial-derived cells contribute to neointimal formation through endothelial-to-mesenchymal transition (EndMT), which is dependent on early activation of the Smad2/3-Slug signaling pathway. Antagonism of transforming growth factor-β (TGF-β) signaling by TGF-β neutralizing antibody, short hairpin RNA-mediated Smad3 or Smad2 knockdown, Smad3 haploinsufficiency, or endothelial cell-specific Smad2 deletion resulted in decreased EndMT and less neointimal formation compared to controls. Histological examination of postmortem human vein graft tissue corroborated the changes observed in our mouse vein graft model, suggesting that EndMT is operative during human vein graft remodeling. These data establish that EndMT is an important mechanism underlying neointimal formation in interpositional vein grafts, and identifies the TGF-β-Smad2/3-Slug signaling pathway as a potential therapeutic target to prevent clinical vein graft stenosis.
    Science translational medicine 03/2014; 6(227):227ra34. DOI:10.1126/scitranslmed.3006927 · 14.41 Impact Factor
  • Michael Joner · Renu Virmani
    Coronary artery disease 03/2014; 25(2):91-3. DOI:10.1097/MCA.0000000000000087 · 1.30 Impact Factor
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    ABSTRACT: This review offers insight into the possible role of vasa vasorum in the development of intracranial vascular disease. Unique structural features of intracranial vessels and nourishment from the surrounding cerebrospinal fluid environment may account for the relative lack of intracranial vasa vasorum early in life. However, with advancing age and with the development of vascular disease, vasa vasorum are known to develop. Advanced contrast material-enhanced imaging techniques are capable of helping detect and even grade intracranial vasa vasorum, and this may provide new insights into our ability to diagnose and assess the risk of intracranial vascular lesions such as atherosclerosis, aneurysms, dissections, and vasculitis. © RSNA, 2013.
    Radiology 06/2013; 267(3):667-679. DOI:10.1148/radiol.13112310 · 6.21 Impact Factor
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    ABSTRACT: Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation and migration followed by remodeling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, transition from a contractile to a synthetic phenotype and the molecular mechanism responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles heal of interventional cardiologists.
    Cardiovascular Research 05/2013; 99(2). DOI:10.1093/cvr/cvt115 · 5.81 Impact Factor
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    ABSTRACT: The primary purpose of this investigation was to determine whether ApoE(-/-) mice, when subjected to chronic stress, exhibit lesions characteristic of human vulnerable plaque and, if so, to determine the time course of such changes. We found that the lesions were remarkably similar to human vulnerable plaque, and that the time course of lesion progression raised interesting insights into the process of plaque development. Lard-fed mixed-background ApoE(-/-) mice exposed to chronic stress develop lesions with large necrotic core, thin fibrous cap and a high degree of inflammation. Neovascularization and intraplaque hemorrhage are observed in over 80% of stressed animals at 20 weeks of age. Previously described models report a prevalence of only 13% for neovascularization observed at a much later time point, between 36 and 60 weeks of age. Thus, our new stress-induced model of advanced atherosclerotic plaque provides an improvement over what is currently available. This model offers a tool to further investigate progression of plaque phenotype to a more vulnerable phenotype in humans. Our findings also suggest a possible use of this stress-induced model to determine whether therapeutic interventions have effects not only on plaque burden, but also, and importantly, on plaque vulnerability.
    Disease Models and Mechanisms 01/2013; 6(2). DOI:10.1242/dmm.009977 · 5.54 Impact Factor
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    ABSTRACT: Biomechanical models are used extensively to study risk factors, such as peak stresses, for vulnerable atherosclerotic plaque rupture. Typically, 3D patient-specific arterial models are reconstructed by interpolating between cross sectional contour data which have a certain axial sampling, or image, resolution. The influence of the axial sampling resolution on computed stresses, as well as the comparison of 3D with 2D simulations, is quantified in this study. A set of histological data of four atherosclerotic human coronary arteries was used which were reconstructed in 3D with a high sampling (HS) and low sampling (LS) axial resolution, and 4 slices were treated separately for 2D simulations. Stresses were calculated using finite element analysis (FEA). High stresses were found in thin cap regions and regions of thin vessel walls, low stresses were found inside the necrotic cores and media and adventitia layers. Axial sampling resolution was found to have a minor effect on general stress distributions, peak plaque/cap stress locations and the relationship between peak cap stress and minimum cap thickness. Axial sampling resolution did have a profound influence on the error in computed magnitude of peak plaque/cap stresses (±15.5% for HS vs. LS geometries and ±24.0% for HS vs. 2D geometries for cap stresses). The findings of this study show that axial under sampling does not influence the qualitative stress distribution significantly but that high axially sampled 3D models are needed when accurate computation of peak stress magnitudes is required.
    Journal of Biomechanics 12/2012; 46(4). DOI:10.1016/j.jbiomech.2012.11.042 · 2.75 Impact Factor
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    ABSTRACT: OBJECTIVE: Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process. METHODS AND RESULTS: Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE(-/-) mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-β and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size. CONCLUSIONS: Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE(-/-) mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.
    Arteriosclerosis Thrombosis and Vascular Biology 12/2012; 33(2). DOI:10.1161/ATVBAHA.112.300543 · 5.53 Impact Factor
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    ABSTRACT: Unstable carotid plaques cause cerebral emboli. Leptin promotes atherosclerosis and vessel wall remodeling. We hypothesized that carotid atherosclerotic lesion instability is associated with local leptin synthesis. Carotid endarterectomy plaques from symptomatic (n=40) and asymptomatic patients with progressive stenosis (n=38) were analyzed for local expression of leptin, tumor necrosis factor (TNF)-α, and plasminogen activator inhibitor type 1. All lesions exhibited advanced atherosclerosis inclusive of thick- and thin-cap fibroatheromas or lesion rupture. Symptomatic lesions exhibited more plaque ruptures and macrophage infiltration (P=0.001 and P=0.05, respectively). Symptomatic plaques showed preferential leptin, TNF-α, and plasminogen activator inhibitor type 1 transcript (P=0.03, P=0.04, and P=0.05, respectively). Leptin mRNA and antigen in macrophages and smooth muscle cells were confirmed by in situ hybridization and immunohistochemistry. Plasma leptin levels were not significantly different between groups (P=1.0), whereas TNF-α was significantly increased in symptomatic patients (P=0.006). Human aortic smooth muscle cell culture stimulated by TNF-α, lipopolysaccharide, or lipoteichoic acid revealed 6-, 6.7-, and 6-fold increased secreted leptin antigen, respectively, at 72 hours (P<0.05). Neurologically symptomatic patients overexpress leptin mRNA and synthesize leptin protein in carotid plaque macrophages and smooth muscle cells. Local leptin induction, presumably by TNF-α, could exert paracrine or autocrine effects, thereby contributing to the pathogenesis of lesion instability. URL: www.Clinicaltrials.gov. Unique identifier: NCT00449306.
    Journal of the American Heart Association 10/2012; 1(5):e001727. DOI:10.1161/JAHA.112.001727 · 2.88 Impact Factor
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    ABSTRACT: Drug-coated balloon (DCB) technology has emerged as a promising therapy particularly in the treatment of coronary in-stent restenosis. Although a variety of devices are available for clinical use, clinical outcomes have been variable and scope for significant improvement exists. In a preclinical study, a total of 10 juvenile healthy farm pigs underwent catheter-based DCB deployment in coronary arteries with angiographic and pathological follow-up at 7 or 28 days. Animals were randomly allocated to the PRIMUS or Dior® DCB (N.=10 per group) and evaluated by histopathology and morphometric analysis. In a first-in-man clinical study a total of 19 consecutive patients presenting with restenosis within drug-eluting stents were treated with the PRIMUS DCB. Clinical follow-up was performed out to 6 months. Neointimal thickness was similar between the PRIMUS and Dior® DCB groups, while fibrin deposition and inflammation were more sustained in the PRIMUS group at 28 days. In 19 consecutive patients presenting with in-stent restenosis of drug-eluting stents, treatment with the PRIMUS DCB catheter resulted in high procedural efficacy. There were no adverse clinical events observed out to 6 months. The PRIMUS DCB demonstrates high preclinical safety and excellent acute performance and safety. Further studies are needed to delineate the relative merits of this novel DCB compared to other devices.
    Minerva cardioangiologica 10/2012; 60(5):507-15. · 0.48 Impact Factor
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    ABSTRACT: The relationships between oxidation-specific epitopes (OSE), lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture has not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apolipoprotein B-100, oxidized phospholipids (OxPL), apolipoprotein (a) [apo(a)] and malondialdehyde-lysine (MDA), MDA-related epitopes with antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft (SVG) distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL and IK17 epitopes increased proportionally, but differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools and the necrotic core and most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans.
    The Journal of Lipid Research 09/2012; 53(12). DOI:10.1194/jlr.P030890 · 4.73 Impact Factor
  • ASME 2012 Summer Bioengineering Conference; 06/2012
  • ASME 2012 Summer Bioengineering Conference; 06/2012
  • S K Yazdani · F D Kolodgie · R Virmani
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    ABSTRACT: Although drug-eluting stents (DES) have significantly reduced the rates of restenosis as compared to bare metal stents, late stent thrombosis remains a major drawback, especially for "off-label" use. Delayed arterial healing, characterized by persistent fibrin deposition and poor endothelialization, has been shown to correlate with late DES thrombosis. To overcome these limitations, a "pro-healing" approach has been developed to capture circulating endothelial progenitor cells (EPC) to enhance endothelialization of the stent surface. EPC have the ability to migrate to sites of vascular injury and aid the regeneration of damaged and dysfunctional endothelium. Clinically, the safety of EPC-capture stent has been proven in numerous clinical trials with low incidence of late stent thrombosis. The focus of this review is to demonstrate the efficacy of the Genous stent in preclinical studies, specifically to show the effectiveness of the anti-CD34+ coating in promoting endothelialization and reducing thrombogenicity.
    Minerva cardioangiologica 02/2012; 60(1):11-21. · 0.48 Impact Factor

Publication Stats

2k Citations
376.92 Total Impact Points

Institutions

  • 2008–2015
    • CVPath Institute
      GAI, Maryland, United States
  • 2006–2010
    • Johns Hopkins Medicine
      • Department of Radiology and Radiological Science
      Baltimore, Maryland, United States
    • Hippokration General Hospital, Athens
      Athínai, Attica, Greece
  • 2007
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 2001–2005
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 2003
    • Case Western Reserve University
      Cleveland, Ohio, United States