Calcium Sensitizer EMD 57033, but Not the Beta1-adrenoreceptor Agonist Dobutamine, Increases Mechanical Efficiency in Stunned Myocardium

Journal of Cardiovascular Pharmacology. Jan, 2002  |  Pubmed ID: 11743229

External work, efficiency of energy transfer (EET), and mechanical efficiency (defined as the ratio of external work over myocardial oxygen consumption (MVO2) are reduced in stunned myocardium. We therefore evaluated how inotropic stimulation by dobutamine and the calcium sensitizer EMD 57033 affected the regional stress-strain relationship as, from which contractility (E(es)), external work at the working point (EWwp), maximal external work (EWmax), EETwp (%), and EETmax are determined. Thirty minutes after regional stunning in 11 open chest pigs by two 10-min coronary occlusions separated by 10 min of reperfusion, dobutamine (0.5, 1, and 2 microg x kg(-1) x min(-1)) was infused, after an ample washout period followed by infusion of EMD 57033 (0.05, 0.1, 0.2 mg x kg(-1) x min(-1)). Stunning decreased E(es) (30%), EWwp (56%), EWmax (63%), EETwp (34%), EETmax (33%) and mechanical efficiency (55%), but MVO2 was unaffected. EWwp, EWmax, EETwp, and EETmax increased similarly with the two drugs, whereas MVO2 increased only after dobutamine. Consequently, mechanical efficiency increased linearly with contractility during EMD 57033 infusion but remained constant during infusion of dobutamine.

Images in Cardiovascular Medicine. Focal In-stent Restenosis Near Step-up: Roles of Low and Oscillating Shear Stress?

Circulation. Jun, 2002  |  Pubmed ID: 12057999

High Shear Stress After Successful Balloon Angioplasty is Associated with Restenosis and Target Lesion Revascularization

American Heart Journal. Jul, 2002  |  Pubmed ID: 12094200

Vascular wall shear stress (WSS) has been implied in the pathogenesis of atherosclerosis and vascular remodeling. Our aim was to calculate WSS after balloon angioplasty and evaluate its predictive value for long-term outcome.

Shear Stress, Vascular Remodeling and Neointimal Formation

Journal of Biomechanics. May, 2003  |  Pubmed ID: 12694998

The role of shear stress in atherosclerosis has been well documented. However, its role in restenosis was underexposed. In this paper a novel in vivo measuring technique and several of its applications related to restenosis will be described. The technique consists of a combination of 3D reconstruction of blood vessels and computational fluid dynamics (CFD). The 3D imaging techniques use either of 3D intravascular ultrasound (IVUS) as a stand-alone technique or a fusion of biplane angiography and IVUS (ANGUS). CFD is applied in order to relate local shear stress distribution to the morphology of the vessel wall. In the applications of these techniques it will be demonstrated that shear stress plays a role in the prediction of neointimal formation in in-stent restenosis and in vascular remodeling after balloon angioplasty. Attempts to locally increase shear stress by a newly developed flow divider indicate that shear stress reduce in-stent neointimal formation by 50%.

Augmentation of Wall Shear Stress Inhibits Neointimal Hyperplasia After Stent Implantation: Inhibition Through Reduction of Inflammation?

Circulation. Jun, 2003  |  Pubmed ID: 12742998

Low wall shear stress (WSS) increases neointimal hyperplasia (NH) in vein grafts and stents. We studied the causal relationship between WSS and NH formation in stents by locally increasing WSS with a flow divider (Anti-Restenotic Diffuser, Endoart SA) placed in the center of the stent.

Inflammation and Atherosclerosis: Mechanisms Underlying Vulnerable Plaque

Journal of Interventional Cardiology. Apr, 2003  |  Pubmed ID: 12768913

Extension of Increased Atherosclerotic Wall Thickness into High Shear Stress Regions is Associated with Loss of Compensatory Remodeling

Circulation. Jul, 2003  |  Pubmed ID: 12821552

Atherosclerosis preferentially develops at average low shear stress (SS) locations. SS-related signaling maintains lumen dimensions by inducing outward arterial remodeling. Prolonged plaque accumulation at low SS predilection locations explains an inverse relation between wall thickness (WT) and SS. No data exist on WT-SS relations when lumen narrowing and loss of compensatory remodeling commence.

Functional Expression of Endothelial Nitric Oxide Synthase Fused to Green Fluorescent Protein in Transgenic Mice

The American Journal of Pathology. Oct, 2003  |  Pubmed ID: 14507674

The activity of endothelial nitric oxide synthase (eNOS) is subject to complex transcriptional and post-translational regulation including the association with several proteins and variations in subcellular distribution. In the present study we describe a transgenic mouse model expressing eNOS fused to green fluorescent protein (GFP), which allows the study of localization and regulation of eNOS expression. We tested the functionality of eNOS in the eNOS-GFP mice. Expression of eNOS was restricted to the endothelial lining of blood vessels in various tissues tested, without appreciable expression in non-endothelial cells. Activity of the enzyme was confirmed by assaying the conversion of L-arginine to L-citrulline. NO production in isolated vessels was increased in transgenic mice when compared to non-transgenic control animals (4.88 +/- 0.59 and 2.48 +/- 0.47 micro mol/L NO, respectively, P < 0.005). Both the mean aortic pressure and the pulmonary artery pressure were reduced in eNOS-GFP mice (both approximately 30%, P < 0.05). Plasma cholesterol levels were also slightly reduced ( approximately 20%, P < 0.05). In conclusion, eNOS-GFP mice express functional eNOS and provide a unique model to study regulation of eNOS activity or eNOS-mediated vascular events, including response to ischemia, response to differences in shear stress, angiogenesis and vasculogenesis, and to study the subcellular distribution in relation with functional responses to these events.

The Effect of Reduced Blood-flow on the Coronary Wall Temperature. Are Significant Lesions Suitable for Intravascular Thermography?

European Heart Journal. Oct, 2003  |  Pubmed ID: 14522575

The purpose of this study was to investigate the relation between acute coronary flow reduction and arterial wall temperature.

Intravascular Thermography: Immediate Functional and Morphological Vascular Findings

European Heart Journal. Jan, 2004  |  Pubmed ID: 14720533

To investigate safety, feasibility, and injurious effect on endothelial cells of a thermography catheter as well as effect of flow on measured temperature in non-obstructive arteries.

Diastolic Coronary Vascular Reserve: a New Index to Detect Changes in the Coronary Microcirculation in Hypertrophic Cardiomyopathy

Journal of the American College of Cardiology. Feb, 2004  |  Pubmed ID: 14975481

The present study introduces a modification of the diastolic coronary conductance concept that maintains its sensitive properties to detect changes in the coronary microcirculation in human hypertrophy.

The Role of Shear Stress in Atherosclerosis: Action Through Gene Expression and Inflammation?

Cell Biochemistry and Biophysics. 2004  |  Pubmed ID: 15475614

Atherosclerotic lesions preferentially localize near side branches or curved vessels. During the last few decades, research has been shown that low or low and oscillating shear stress is associated with plaque location. Despite ample evidence, the precise mechanism is unknown. This is mainly because of a lack of appropriate animal models. We describe two novel methods to study the hypothesis that shear stress acts through endothelial gene expression or shear stress acts through localizing of inflammation. Both literature evidence and own findings support a role for both mechanisms in atherosclerosis.

Letter Regarding Article by Korshunov and Berk, "Strain-dependent Vascular Remodeling: the 'Glagov Phenomenon' is Genetically Determined"

Circulation. Mar, 2005  |  Pubmed ID: 15753223

Geometry Guided Data Averaging Enables the Interpretation of Shear Stress Related Plaque Development in Human Coronary Arteries

Journal of Biomechanics. Jul, 2005  |  Pubmed ID: 15922767

The average low shear stress (SS) is known to determine predilection sites of atherosclerotic plaques. However, as plaques encroach into the lumen and thereby increase SS, interpretation of patient-specific data obtained at one moment in time regarding the influence of SS in the generation of atherosclerosis is not straightforward. This study aims to compare two methods of data analysis for the aid of data interpretation: (a) point-wise analysis of the raw data, (b) global analysis: to assess the history related natural SS distribution in coronary arteries by averaging the data in the axial vessel direction. Normal to mildly diseased human coronary arteries were investigated applying a combination of 3-D reconstruction technique and computational fluid dynamics (CFD). Point-wise analysis relating local wall thickness to local SS showed in only 4% of the cases an inverse relationship. In contrast, averaging the data in the axial vessel direction, showed in 38% a significant inverse relation between wall thickness and SS, resulting in an average negative slope of -0.70+/-0.46 mm/Pa. These data suggest that using a geometry guided way of data averaging may reveal history related effects of SS, which in part explains localization of atherosclerotic plaques.

Shear Stress Affects the Intracellular Distribution of ENOS: Direct Demonstration by a Novel in Vivo Technique

Blood. Dec, 2005  |  Pubmed ID: 16105973

The focal location of atherosclerosis in the vascular tree is correlated with local variations in shear stress. We developed a method to induce defined variations in shear stress in a straight vessel segment of a mouse. To this end, a cylinder with a tapered lumen was placed around the carotid artery, inducing a high shear stress field. Concomitantly, regions of low shear stress and oscillatory shear stress were created upstream and down-stream of the device, respectively. This device was used in mice transgenic for an eNOS3GFP fusion gene. We observed a strong induction of endothelial nitric oxide synthase-green fluorescent protein (eNOS-GFP) mRNA expression in the high shear stress region compared with the other regions (P < .05). Quantification of eNOS-GFP fluorescence or of immunoreactivity to the Golgi complex or to platelet endothelial cell adhesion molecule 1 (PECAM-1) showed an increase in the high shear stress region (P < .05) compared with nontreated carotid arteries. Colocalization of eNOS-GFP with either the Golgi complex or PECAM-1 also responded to alterations of shear stress. In conclusion, we showed a direct response of mRNA and protein expression in vivo to induced variations of shear stress. This model provides the opportunity to study the relationship between shear stress alterations, gene expression, and atherosclerosis.

Myocardial Contractility Does Not Determine the Haemodynamic Response During Dialysis

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. Nov, 2005  |  Pubmed ID: 16115849

LV systolic dysfunction in dialysis patients has been implicated in the genesis of dialysis hypotension. End-systolic elastance (E(es)), a relatively load-independent parameter of myocardial contractility, was assessed by testing the acute left ventricular (LV) response to nitroglycerine (NTG) in hypotension-prone (HP) and hypotension-resistant (HR) patients.

In Vivo Temperature Heterogeneity is Associated with Plaque Regions of Increased MMP-9 Activity

European Heart Journal. Oct, 2005  |  Pubmed ID: 16144779

Plaque rupture has been associated with a high matrix metalloproteinase (MMP) activity. Recently, regional temperature variations have been observed in atherosclerotic plaques in vivo and ascribed to the presence of macrophages. As macrophages are a major source of MMPs, we examined whether regional temperature changes are related to local MMP activity and macrophage accumulation.

Three-dimensional Palpography of Human Coronary Arteries. Ex Vivo Validation and In-patient Evaluation

Herz. Mar, 2005  |  Pubmed ID: 16493546

Rupture of thin-cap fibroatheroma is a major cause of acute myocardial infarction and stroke. Identification of these plaques is one of the major challenges in cardiovascular medicine. At present, techniques with sufficient sensitivity and specificity to identify these unstable plaques are not clinically available. This paper describes a new technique to identify these plaques.

Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress

Circulation. Jun, 2006  |  Pubmed ID: 16754802

Atherosclerotic lesions are predominantly observed in curved arteries and near side branches, where low or oscillatory shear stress patterns occur, suggesting a causal connection. However, the effect of shear stress on plaque vulnerability is unknown because the lack of an appropriate in vivo model precludes cause-effect studies.

Intravascular Ultrasound Tissue Harmonic Imaging in Vivo

IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control. Oct, 2006  |  Pubmed ID: 17036792

Tissue harmonic imaging (THI) has been shown to increase image quality of medical ultrasound in the frequency range from 2 to 10 MHz and might, therefore, also be used to improve image quality in intravascular ultrasound (IVUS). In this study we constructed a prototype IVUS system that could operate in both fundamental frequency and second harmonic imaging modes. This system uses a conventional, continuously rotating, single-element IVUS catheter and was operated in fundamental 20 MHz, fundamental 40 MHz, and harmonic 40 MHz modes (transmit 20 MHz, receive 40 MHz). Hydrophone beam characterization measurements demonstrated the build-up of a second harmonic signal as a function of increasing pressure. Imaging experiments were conducted in both a tissue-mimicking phantom and in an atherosclerotic animal model in vivo. Acquisitions of fundamental 20 and 40 MHz and second harmonic acquisitions resulted in cross sections of the phantom and a rabbit aorta. The harmonic results of the imaging experiments showed the feasibility of intravascular THI with a conventional IVUS catheter both in a phantom and in vivo. The harmonic acquisitions also showed the potential of THI to reduce image artifacts compared to fundamental imaging.

Harmonic Intravascular Ultrasound Imaging with a Dual-frequency Catheter

Ultrasound in Medicine & Biology. Nov, 2006  |  Pubmed ID: 17112951

Recent studies have shown the feasibility of tissue and contrast harmonic imaging with a prototype nonlinear intravascular ultrasound (IVUS) system using a conventional single-element rotating IVUS catheter. In this study, a dual-frequency transducer element was mounted in an IVUS catheter and its second harmonic imaging performance was investigated and compared with that of a conventional IVUS catheter. Hydrophone measurements showed a transmit efficiency improvement of >6 dB for the dual-frequency catheter at 20 MHz. In vitro phantom experiments showed a signal-to noise ratio improvement of >5 dB in second harmonic mode at 40 MHz (H40) with the dual-frequency catheter, when using equal transmit voltage for both catheters. Finally, in vivo experiments were conducted and showed image improvement in H40 acquisitions with respect to the conventional IVUS catheter.

Norepinephrine-induced Vasoconstriction Results in Decreased Blood Volume in Dialysis Patients

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. May, 2006  |  Pubmed ID: 16449290

Hypotension during haemodialysis results from an inadequate cardiovascular response to ultrafiltration-induced hypovolaemia. It has been suggested that plasma volume could be increased as a result of systemic vasoconstriction.

Large Variations in Absolute Wall Shear Stress Levels Within One Species and Between Species

Atherosclerosis. Dec, 2007  |  Pubmed ID: 17169362

Wall shear stress (WSS), the frictional force between blood and endothelium, is an important determinant of vascular function. It is generally assumed that WSS remains constant at a reference value of 15 dyn/cm(2). In a study of small rodents, we realized that this assumption could not be valid. This review presents an overview of recent studies in large and small animals where shear stress was measured, derived from velocity measurements or otherwise, in large vessels. The data show that large variations exist within a single species (human: variation of 2-16 N/m(2)). Moreover, when we compared different species at the same location within the arterial tree, an inverse relationship between animal size and wall shear stress was noted. When we related WSS to diameter, a unique relationship was derived for all species studied. This relationship could not be described by the well-known r(3) law of Murray, but by the r(2) law introduced by Zamir et al. in 1972. In summary, by comparing data from the literature, we have shown that: (i) the assumption of a physiological WSS level of approximately 15 dyn/cm(2) for all straight vessels in the arterial tree is incorrect; (ii) WSS is not constant throughout the vascular tree; (iii) WSS varies between species; (iv) WSS is inversely related to the vessel diameter. These data support an "r(2) law" rather than Murray's r(3) law for the larger vessels in the arterial tree.

Gelatinolytic Activity in Atherosclerotic Plaques is Highly Localized and is Associated with Both Macrophages and Smooth Muscle Cells in Vivo

Circulation. Feb, 2007  |  Pubmed ID: 17242283

Atherosclerosis is considered an inflammatory disease. Recent studies provided evidence for a predominant upstream location of plaque inflammation. The present study introduces a novel technique that evaluates the underlying mechanism of this spatial organization.

Shear Stress-induced Changes in Atherosclerotic Plaque Composition Are Modulated by Chemokines

The Journal of Clinical Investigation. Mar, 2007  |  Pubmed ID: 17304353

We previously found that low shear stress (LSS) induces atherosclerotic plaques in mice with increased lipid and matrix metalloproteinase content and decreased vascular smooth muscle and collagen content. Here, we evaluated the role of chemokines in this process, using an extravascular device inducing regions of LSS, high shear stress, and oscillatory shear stress (OSS) in the carotid artery. One week of shear stress alterations induced expression of IFN-gamma-inducible protein-10 (IP-10) exclusively in the LSS region, whereas monocyte chemoattractant protein-1 (MCP-1) and the mouse homolog of growth-regulated oncogene alpha (GRO-alpha) were equally upregulated in both LSS and OSS regions. After 3 weeks, GRO-alpha and IP-10 were specifically upregulated in LSS regions. After 9 weeks, lesions with thinner fibrous caps and larger necrotic cores were found in the LSS region compared with the OSS region. Equal levels of MCP-1 expression were observed in both regions, while expression of fractalkine was found in the LSS region only. Blockage of fractalkine inhibited plaque growth and resulted in striking differences in plaque composition in the LSS region. We conclude that LSS or OSS triggers expression of chemokines involved in atherogenesis. Fractalkine upregulation is critically important for the composition of LSS-induced atherosclerotic lesions.

Assessment of Unstable Atherosclerosis in Mice

Arteriosclerosis, Thrombosis, and Vascular Biology. Apr, 2007  |  Pubmed ID: 17332492

There is an urgent need for representative animal models where prospective examination of the events leading up to plaque rupture and the rupture process itself can be performed. Recently, reports have begun to emerge that apolipoprotein E and low density lipoprotein receptor knockout mice may spontaneously develop unstable atherosclerosis, with plaques in certain parts of the arterial tree showing features suggestive of plaque rupture. Here we discuss the problems inherent in applying definitions of plaque rupture as seen in human arteries to mice; the anatomic locations in mice where unstable plaques do and do not occur; methods of inducing plaque instability in mice; and how to assess plaque stability in mice. These considerations lead us to a number of general recommendations.

Effect of Shear Stress on Vascular Inflammation and Plaque Development

Current Opinion in Lipidology. Oct, 2007  |  Pubmed ID: 17885423

This review describes evidence that shear stress acts through modulation of inflammation and by that process affects atherogenesis and plaque composition.

Rapamycin Modulates the ENOS Vs. Shear Stress Relationship

Cardiovascular Research. Apr, 2008  |  Pubmed ID: 18079107

Studies in animals and patients indicate that rapamycin affects vasodilatation differently in outer and inner curvatures of blood vessels. We evaluated in this study whether rapamycin affects endothelial nitric oxide synthase (eNOS) responsiveness to shear stress under normo- and hypercholesteraemic conditions to explain these findings.

Atherosclerosis: Cell Biology and Lipoproteins - New Developments in Imaging of Inflammation of the Vulnerable Plaque

Current Opinion in Lipidology. Feb, 2008  |  Pubmed ID: 18196994

Increased Endothelial Mitogen-activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis

Circulation Research. Sep, 2008  |  Pubmed ID: 18723442

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.

Hemodynamic Parameters Regulating Vascular Inflammation and Atherosclerosis: a Brief Update

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. Oct, 2008  |  Pubmed ID: 18757166

Atherosclerosis is a chronic lipid-driven inflammatory disease of the arteries. Early lesions (fatty streaks) contain monocytes and T lymphocytes which are recruited from the circulation by adhesion to activated vascular endothelial cells (EC). This process is described as the leukocyte adhesion cascade. Atherogenesis occurs predominantly at branches and bends of the arterial tree that are exposed to relatively low or re-circulating blood flow. Here we briefly review the effects of blood flow and shear stress on the leukocyte adhesion cascade and endothelial cell function.

Endothelial Primary Cilia in Areas of Disturbed Flow Are at the Base of Atherosclerosis

Atherosclerosis. Feb, 2008  |  Pubmed ID: 17631294

Atherosclerosis develops in the arterial system at sites of low as well as low and oscillating shear stress. Previously, we demonstrated a shear-related distribution of ciliated endothelial cells in the embryonic cardiovascular system and postulated that the primary cilium is a component of the shear stress sensor, functioning as a signal amplifier. This shear-related distribution is reminiscent of the atherosclerotic predilection sites. Thus, we determined whether a link exists between location and frequency of endothelial primary cilia and atherogenesis. We analyzed endothelial ciliation of the adult aortic arch and common carotid arteries of wild type C57BL/6 and apolipoprotein-E-deficient mice. Primary cilia are located at the atherosclerotic predilection sites, where flow is disturbed, in wild type mice and they occur on and around atherosclerotic lesions in apolipoprotein-E-deficient mice, which have significantly more primary cilia in the aortic arch than wild type mice. In addition, common carotid arteries were challenged for shear stress by application of a restrictive cast, resulting in the presence of primary cilia only at sites of induced low and disturbed shear. In conclusion, these data relate the presence of endothelial primary cilia to regions of atherogenesis, where they increase in number under hyperlipidemia-induced lesion formation. Experimentally induced flow disturbance leads to induction of primary cilia, and subsequently to atherogenesis, which suggests a role for primary cilia in endothelial activation and dysfunction.

Atherosclerosis: Cell Biology and Lipoproteins--shear Stress and Inflammation in Plaque Formation: New Evidence

Current Opinion in Lipidology. Dec, 2008  |  Pubmed ID: 18957888

Pulmonary Artery Size and Function After Fontan Operation at a Young Age

Journal of Magnetic Resonance Imaging : JMRI. Nov, 2008  |  Pubmed ID: 18972351

To assess pulmonary artery (PA) size, flow variables, and wall shear stress (WSS) in patients after Fontan operation at a young age.

Personalised Imaging and Biomechanical Modelling of Large Vessels

Medical & Biological Engineering & Computing. Nov, 2008  |  Pubmed ID: 18987903

A Primer on the Immune System in the Pathogenesis and Treatment of Atherosclerosis

EuroIntervention : Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. Nov, 2008  |  Pubmed ID: 19110813

Atherosclerosis is currently appreciated as a disease with a large inflammatory component. The underlying mechanisms, which are uncovered in a rapid pace, are greatly interconnected and as such very complex. Nevertheless, for clinicians it is important have some degree of insight in these immunologic mechanisms in order to interpret the current research advances. The aim of this review is to supply clinicians with this knowledge, avoiding too much detail. All the relevant immunologic basics will be discussed at first, followed by the immunity related theories of atherosclerosis. Finally, current and new immune-modulatory therapies will be discussed.

Donor Pre-treatment with Tacrolimus Reduces Transplant Vasculopathy

Pharmacological Research : the Official Journal of the Italian Pharmacological Society. Apr, 2009  |  Pubmed ID: 19162189

We tested whether transplant arteriosclerosis can be reduced by pre-treatment of the donor with immunosuppressive agents, using a rat allogeneic aorta transplantation model. Donor rats received no pre-treatment, or tacrolimus, methylprednisolone, rapamycin, or mycofenolate mofetil (MMF) 16 and 2h before explantation of the grafts. Eight weeks after transplantation, aorta allografts were harvested. Percent intima area/intima+media area (I/I+M), inflammatory cells and in situ MMP-2 and -9 activity were determined. In pre-transplantation biopsies, MMP-2 and -9 ratio, and mRNA levels for genes of interest were determined. In pre-transplantation biopsies we found no differences in MMP-2/9 ratio, and Bcl-2, Bax, TGF-beta, HO-1, p21, and HIF-1alpha mRNA expression between the groups. Aorta allografts, pre-treated with tacrolimus, showed significantly lower I/I+M ratio compared to untreated controls (p<0.01). Pre-treatment with methylprednisolone, rapamycin or MMF did not significantly reduce I/I+M ratio. In situ MMP-2/MMP-9 activity was significantly reduced in grafts treated with tacrolimus and rapamycin compared to controls (p<0.05). Immunohistochemistry revealed a high number of CD4+ cells and high CD4/CD8 ratio in grafts pre-treated with tacrolimus. Donor pre-treatment with tacrolimus significantly reduces transplant arteriosclerosis and is associated with reduced in situ MMP-2/MMP-9 activity and increased number of CD4+ cells.

Activation of MMP8 and MMP13 by Angiotensin II Correlates to Severe Intra-plaque Hemorrhages and Collagen Breakdown in Atherosclerotic Lesions with a Vulnerable Phenotype

Atherosclerosis. May, 2009  |  Pubmed ID: 19233360

Angiotensin II (ATII)-mediated hypertension increases the risk for acute coronary events, which may be caused by augmented collagen degradation. Interstitial fibers of collagen type I in the plaque can be degraded by MMP8 and MMP13 specifically. Indeed high MMP8 levels have been correlated with ruptured plaques in patients. To study the contribution of ATII in plaque rupture, we evaluated its effect on MMP8 and MMP13 activity on the vulnerable lesions using an extravascular device that induces regions of pro-atherogenic shear stress in the carotid arteries of ApoE KO mice. This triggers the growth of lesions with a "vulnerable" macrophage-rich phenotype (referred to as upstream lesions) and lesions with a "stable" fibrotic phenotype (referred to as downstream lesions). ATII administration increased mean blood pressure, and increased the incidence of intra-plaque hemorrhages (IPH) from 30% to 73% of the animals in the upstream segments. The area of IPH was also increased by 5-fold. No IPHs were observed in the downstream lesions of the control group or the ATII group. In addition, ATII treatment doubled the size of upstream and downstream lesions. Upstream lesions in the ATII group were decreased in collagen content by 3-fold, contained 2-fold higher MMP8 and MMP13 levels, with a 2- and 3-fold increase in collagen type I degradation by MMP8 and MMP13 respectively compared to the upstream lesions in the control group. Gene expression analysis showed general increase in procollagens and TIMPs expression in response to ATII. However, ATII also decreased procollagen 5alpha3 expression in downstream lesions and decreased TIMP4 expression in upstream lesions. These data show that ATII promotes a "stable" fibrotic phenotype by inducing severe intra-plaque hemorrhages, characterized by increased degradation of interstitial collagen I via an MMP-mediated (MMP8 and MMP13) mechanism.

Activation of Nrf2 in Endothelial Cells Protects Arteries from Exhibiting a Proinflammatory State

Arteriosclerosis, Thrombosis, and Vascular Biology. Nov, 2009  |  Pubmed ID: 19729611

Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries.

Large Variations in Absolute Wall Shear Stress Levels Within One Species and Between Species

Atherosclerosis. May, 2009  |  Pubmed ID: 18823888

C-Jun N-terminal Kinase Primes Endothelial Cells at Atheroprone Sites for Apoptosis

Arteriosclerosis, Thrombosis, and Vascular Biology. Mar, 2010  |  Pubmed ID: 20056910

Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree. Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites.

MRI-determined Carotid Artery Flow Velocities and Wall Shear Stress in a Mouse Model of Vulnerable and Stable Atherosclerotic Plaque

Magma (New York, N.Y.). Apr, 2010  |  Pubmed ID: 20229088

We report here on the pre-clinical MRI characterization of an apoE-/- mouse model of stable and vulnerable carotid artery atherosclerotic plaques, which were induced by a tapered restriction (cast) around the artery. Specific focus was on the quantification of the wall shear stress, which is considered a key player in the development of the plaque phenotype.

Flow Interactions with Cells and Tissues: Cardiovascular Flows and Fluid-structure Interactions. Sixth International Bio-Fluid Mechanics Symposium and Workshop, March 28-30, 2008, Pasadena, California

Annals of Biomedical Engineering. Mar, 2010  |  Pubmed ID: 20336826

Interactions between flow and biological cells and tissues are intrinsic to the circulatory, respiratory, digestive and genitourinary systems. In the circulatory system, an understanding of the complex interaction between the arterial wall (a living multi-component organ with anisotropic, nonlinear material properties) and blood (a shear-thinning fluid with 45% by volume consisting of red blood cells, platelets, and white blood cells) is vital to our understanding of the physiology of the human circulation and the etiology and development of arterial diseases, and to the design and development of prosthetic implants and tissue-engineered substitutes. Similarly, an understanding of the complex dynamics of flow past native human heart valves and the effect of that flow on the valvular tissue is necessary to elucidate the etiology of valvular diseases and in the design and development of valve replacements. In this paper we address the influence of biomechanical factors on the arterial circulation. The first part presents our current understanding of the impact of blood flow on the arterial wall at the cellular level and the relationship between flow-induced stresses and the etiology of atherosclerosis. The second part describes recent advances in the application of fluid-structure interaction analysis to arterial flows and the dynamics of heart valves.

Microcalcifications in Atherosclerotic Lesion of Apolipoprotein E-deficient Mouse

International Journal of Experimental Pathology. Dec, 2010  |  Pubmed ID: 20804542

Evidence is accumulating that calcium-rich microdeposits in the vascular wall might play a crucial role in the onset and progression of atherosclerosis. Here we investigated an atherosclerotic lesion of the carotid artery in an established murine model, i.e. the apolipoprotein E-deficient (APOE(-/-) ) mouse to identify (i) the presence of microcalcifications, if any, (ii) the elemental composition of microcalcifications with special reference to calcium/phosphorus mass ratio and (iii) co-localization of increased concentrations of iron and zinc with microcalcifications. Atherosclerosis was induced by a flow-divider placed around the carotid artery resulting in low and high shear-stress regions. Element composition was assessed with a proton microprobe. Microcalcifications, predominantly present in the thickened intima of the low shear-stress region, were surrounded by areas with normal calcium levels, indicating that calcium-precipitation is a local event. The diameter of intimal microcalcifications varied from 6 to 70 μm. Calcium/phosphorus ratios of microcalcifications varied from 0.3 to 4.8, mainly corresponding to the ratio of amorphous calcium-phosphate. Increased iron and zinc concentrations commonly co-localized with microcalcifications. Our findings indicate that the atherosclerotic process in the murine carotid artery is associated with locally accumulated calcium, iron and zinc. The calcium-rich deposits resemble amorphous calcium phosphate rather than pure hydroxyapatite. We propose that the APOE(-/-) mouse, in which atherosclerosis was evoked by a flow-divider, offers a useful model to investigate the pathophysiological significance of accumulation of elements such as calcium, iron and zinc.

Contrast Enhancement by Differently Sized Paramagnetic MRI Contrast Agents in Mice with Two Phenotypes of Atherosclerotic Plaque

Contrast Media & Molecular Imaging. Jan-Feb, 2011  |  Pubmed ID: 20882509

Interest in the use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of three differently sized gadolinium-based contrast agents to permeate different mouse plaque phenotypes was evaluated with MRI. A tapered cast was implanted around the right carotid artery of apoE(-/-) mice to induce two different plaque phenotypes: a thin cap fibroatheroma (TCFA) and a non-TCFA lesion. Both plaques were allowed to develop over 6 and 9 weeks, leading to an intermediate and advanced lesion, respectively. Signal enhancement in the carotid artery wall, following intravenous injection of Gd-HP-DO3A as well as paramagnetic micelles and liposomes was evaluated. In vivo T(1) -weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy and correlated to lesion phenotype. The two smallest contrast agents, i.e. Gd-HP-DO3A and micelles, were found to enhance contrast in T(1) -weighted MR images of all investigated plaque phenotypes. Maximum contrast enhancement ranged between 53 and 70% at 6 min after injection of Gd-HP-DO3A with highest enhancement and longest retention in the non-TCFA lesion. Twenty-four hours after injection of micelles maximum contrast enhancement ranged between 24 and 35% in all plaque phenotypes. Administration of the larger liposomes did not cause significant contrast enhancement in the atherosclerotic plaques. Confocal fluorescence microscopy confirmed the MRI-based differences in plaque permeation between micelles and liposomes. Plaque permeation of contrast agents was strongly dependent on size. Our results implicate that, when equipped with targeting ligands, liposomes are most suitable for the imaging of plaque-associated endothelial markers due to low background enhancement, whereas micelles, which accumulate extravascularly on a long timescale, are suited for imaging of less abundant markers inside plaques. Low molecular weight compounds may be employed for target-specific imaging of highly abundant extravascular plaque-associated targets.

Dexamethasone Arterializes Venous Endothelial Cells by Inducing Mitogen-activated Protein Kinase Phosphatase-1: a Novel Antiinflammatory Treatment for Vein Grafts?

Circulation. Feb, 2011  |  Pubmed ID: 21262999

Vein grafting in coronary artery surgery is complicated by a high restenosis rate resulting from the development of vascular inflammation, intimal hyperplasia, and accelerated atherosclerosis. In contrast, arterial grafts are relatively resistant to these processes. Vascular inflammation is regulated by signaling intermediaries, including p38 mitogen-activated protein (MAP) kinase, that trigger endothelial cell (EC) expression of chemokines (eg, interleukin-8, monocyte chemotactic protein-1) and other proinflammatory molecules. Here, we have tested the hypothesis that p38 MAP kinase activation in response to arterial shear stress (flow) may occur more readily in venous ECs, leading to greater proinflammatory activation.

Disturbed Blood Flow Induces RelA Expression Via C-Jun N-terminal Kinase 1: a Novel Mode of NF-κB Regulation That Promotes Arterial Inflammation

Circulation Research. Apr, 2011  |  Pubmed ID: 21350211

The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain.

Stabilisation of Atherosclerotic Plaques. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology

Thrombosis and Haemostasis. Jul, 2011  |  Pubmed ID: 21670845

Plaque rupture and subsequent thrombotic occlusion of the coronary artery account for as many as three quarters of myocardial infarctions. The concept of plaque stabilisation emerged about 20 years ago to explain the discrepancy between the reduction of cardiovascular events in patients receiving lipid lowering therapy and the small decrease seen in angiographic evaluation of atherosclerosis. Since then, the concept of a vulnerable plaque has received a lot of attention in basic and clinical research leading to a better understanding of the pathophysiology of the vulnerable plaque and acute coronary syndromes. From pathological and clinical observations, plaques that have recently ruptured have thin fibrous caps, large lipid cores, exhibit outward remodelling and invasion by vasa vasorum. Ruptured plaques are also focally inflamed and this may be a common denominator of the other pathological features. Plaques with similar characteristics, but which have not yet ruptured, are believed to be vulnerable to rupture. Experimental studies strongly support the validity of anti-inflammatory approaches to promote plaque stability. Unfortunately, reliable non-invasive methods for imaging and detection of such plaques are not yet readily available. There is a strong biological basis and supportive clinical evidence that low-density lipoprotein lowering with statins is useful for the stabilisation of vulnerable plaques. There is also some clinical evidence for the usefulness of antiplatelet agents, beta blockers and renin-angiotensin-aldosterone system inhibitors for plaque stabilisation. Determining the causes of plaque rupture and designing diagnostics and interventions to prevent them are urgent priorities for current basic and clinical research in cardiovascular area.

Jailed Side Branches: Fate of Unapposed Struts Studied with 3D Frequency-domain Optical Coherence Tomography

Journal of Cardiovascular Medicine (Hagerstown, Md.). Aug, 2011  |  Pubmed ID: 21709576

We report the case of a 64-year-old man treated for stable angina with two bare-metal stents in the proximal-mid segment of the left anterior descending artery at the bifurcation with the first diagonal and second septal branches without final kissing balloon dilatation. Seven months later he complained of recurrent angina. Frequency-domain optical coherence tomography (OCT) with three-dimensional (3D) reconstruction was performed, showing a thick rim of neointimal proliferation at the ostium of both branches, causing severe restenosis. Deployment of a stent in a bifurcation main branch without opening the struts at the side-branch ostium may facilitate focal restenosis.

Final Proximal Post-dilatation is Necessary After Kissing Balloon in Bifurcation Stenting

EuroIntervention : Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. Sep, 2011  |  Pubmed ID: 21930464

High rates of restenosis and stent thrombosis are still often observed after bifurcation stenting despite the recommended stent post-dilatation using the kissing balloon (KB) technique. We investigated the potential benefits of a final post-dilatation step in bifurcation stenting with a balloon that respects the natural diameter ratio of the proximal and distal vessels in bifurcations (Murray's law).

Atherosclerotic Plaque Stability Is Affected by the Chemokine CXCL10 in Both Mice and Humans

International Journal of Inflammation. 2011  |  Pubmed ID: 22164344

Background. The chemokine CXCL10 is specifically upregulated during experimental development of plaque with an unstable phenotype. In this study we evaluated the functional consequences of these findings in mice and humans. Methods and Results. In ApoE(-/-) mice, we induced unstable plaque with using a flow-altering device around the carotid artery. From week 1 to 4, mice were injected with a neutralizing CXCL10 antibody. After 9 weeks, CXCL10 inhibition resulted in a more stable plaque phenotype: collagen increased by 58% (P = 0.002), smooth muscle cell content increased 2-fold (P = 0.03), while macrophage MHC class II expression decreased by 50% (P = 0.005). Also, the size of necrotic cores decreased by 41% (P = 0.01). In 106 human carotid endarterectomy specimens we found that increasing concentrations of CXCL10 strongly associate with an increase in atheromatous plaque phenotype (ANOVA, P = 0.003), with high macrophage, low smooth muscle cell, and low collagen content. Conclusions. In the present study we showed that CXCL10 is associated with the development of vulnerable plaque in human and mice. We conclude that CXCL10 might provide a new lead towards plaque-stabilizing therapy.

Kissing Balloon or Sequential Dilation of the Side Branch and Main Vessel for Provisional Stenting of Bifurcations: Lessons from Micro-computed Tomography and Computational Simulations

JACC. Cardiovascular Interventions. Jan, 2012  |  Pubmed ID: 22230150

This study sought to evaluate post-dilation strategies in bifurcation stenting.