Vessel Beds Research Articles

Surgical Technique of Small Bowel Transplantation in a Large Animal Model

An experiment was carried out on pigs during preparation of a clinical project of intestinal transplantation. The objective of this study was to find the best surgical technique of vascular and intestinal anastomosis in different experimental settings (animals with and without immunosuppression) which could have a major impact on everyday veterinary practice. Transplantation was performed in 43 pigs. In the surgical part of the experiment we examined the most suitable surgical technique of vascular anastomosis. A running continuous single-layer seromuscular suture was used for all types of intestinal anastomoses. With regard to vascular anastomosis, the animals were divided into two groups. In group 1 (n = 18) one animal was both donor and recipient of the intestinal graft. Anastomoses were constructed to the mesenteric vessel bed. In group 2 (n = 25), one animal was the graft donor and another was the graft recipient, with revascularization to the central vessel bed. In the second part of the study, we examined the impact of immunosuppressive drug administration on acute cellular rejection and animal survival. Animals that died due to technical failure and reasons unrelated to transplantation were excluded from the evaluation (19 pigs). A total of 24 pigs were included in the second part of the study. The animals were divided into four experimental groups. Group A - autotransplantation (n = 3), group B - allotransplantation on tacrolimus monotherapy (n = 7), group C on combined immunosuppression with tacrolimus and sirolimus (n = 8), and control group D - without immunosuppression (n = 6). Results: A high rate of vascular complications occurred in the first group; 67% (12 out of 18). In the second group, the rate of complications was reduced to 12% (3 out of 25). In the second part of the study the shortest survival was found in group D and the longest in group A. In neither of the immunosuppressed groups (B + C) did we find any significant difference in survival. No complication with the healing of intestinal anastomosis was found in any group. In conclusion we can state the single-layer continuous running suture was safe for all kinds of intestinal anastomoses. Vascular reconstruction to the central vessels was safer for graft survival.

Impact of inactivity and exercise on the vasculature in humans.

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk.

Drug Inhibition of GPIb.

Abstract SCI-38The platelet-specific glycoprotein (GP)Ib, member of the GPIb/IX/V complex, is the main receptor for von Willebrand Factor (VWF), but also for a growing list of other ligands such as thrombin, coagulation factor XI and XII, Mac-1 and P-selectin. For VWF and GPIb to interact, VWF needs to undergo a conformational change. In the circulation, this is induced by shear forces that stretch VWF, especially when bound onto collagen at vascular lesions. As the contribution of VWF to platelet adhesion becomes more important with increasing shear forces, the idea emerged that inhibition of the GPIb-VWF interaction could actually result in an antithrombotic effect targeted to high shear arterioles or stenosed arteries, leaving hemostasis virtually unaffected in vessel beds with slower circulation. And in the mean time, a growing amount of evidence suggests that this could lead to a lower bleeding risk than what is seen with currently available antithrombotic agents. Several compounds have been tested in the past such as fragments of VWF, snake venoms and antibodies. We developed an anti-human GPIb monoclonal antibody, 6B4, that competes directly for the binding site of VWF. The humanized 6B4 Fab-fragment effectively prevented repetitive occlusions of the damaged and stenosed femoral artery in a baboon thrombosis model. Interestingly, only little prolongation of the template bleeding time and minimal increase in blood loss from a standardized incision was observed. This apparent larger therapeutic window of GPIb inhibitors could be particularly useful in ischemic stroke, where the utility of current platelet inhibitors and anticoagulants is significantly counterbalanced by the risk of intracerebral bleeding complications. Recent promising results in a mouse model of cerebral ischemia/reperfusion indeed show a significantly less severe stroke outcome using a GPIb-inhibitor, either administered before or, importantly, after cerebral artery occlusion. No increase in intracerebral hemorrhages was detected, in contrast to what is seen with e.g. GPIIb/IIIa inhibition. Finally, as antibodies may be useful for acute treatments but not for chronic applications, the identification of a GPIb-inhibiting nonamer peptide raises hopes towards development of orally available small molecule inhibitors. DisclosuresNo relevant conflicts of interest to declare.

The pro-angiogenic factor CCN1 enhances the re-endothelialization of biological vascularized matrices in vitro

A problem in generating artificial tissues is supplying nutrients to cells within 3D constructs. The use of a decellularized biological vascularized matrix with preserved pedicles (BioVaM), as a scaffold, appears to aid the generation of perfusable tissue constructs in vitro. To prevent vessel occlusion upon implantation, a functional endothelium must line the graft vessel bed. Here we tested whether the pro-angiogenic factor CCN1 could improve the re-endothelialization of BioVaM in vitro. BioVaM vessel beds were incubated with 100 ng/mL recombinant human CCN1. Human cord blood endothelial cells (hCBEC) were analysed with respect to adhesion behaviour upon CCN1 exposure and seeded onto vessel structures of CCN1 exposed BioVaM (cBioVaM). BioVaMs were fixed in a bioreactor and perfusion cultured for 4 and 14 days (d). BioVaM without CCN1 treatment served as controls. Initial seeding success and endothelialization progression were monitored by fluorescence-labelled hCBEC. During construct cultivation, pH and lactate production were measured. Degree of endothelialization and characterization of seeded cells, with respect to endothelial markers, were investigated histologically. BioVaM vessel structures showed a 78 +/- 17% increase of attached cells when pre-treated with CCN1. Evaluation of re-endothelialization (arbitrary units) was 4.0 +/- 0.8 and 2.6 +/- 0.8 after 4 d, and 5.0 +/- 0.0 and 3.0 +/- 0.5 after 14 d in cBioVaM vs. BioVaM, respectively. On day 14, lactate concentration, an indicator of metabolic activity, was increased 12-fold in cBioVaM relative to BioVaM. A preserved endothelial phenotype of seeded cells was verified in all cultures by acetylated low density lipoprotein uptake and positive immunohistochemistry against von Willebrand factor, endothelial nitric oxide synthase, and CD31. Coating of decellularized vessel structures with CCN1 supports adhesion of hCBEC and enhances re-endothelialization of BioVaM. Perfusable, endothelialized constructs may aid in solving the problem of nourishing cells inside 3D tissue-engineered constructs.

Evaluation of desloratadine on conjunctival allergen challenge‐induced ocular symptoms

Allergic conjunctivitis (AC) is frequently associated with allergic rhinitis (AR) and affects up to 91% of patients with AR. Desloratadine, an orally administered, non-sedating second-generation antihistamine, has proven efficacy and safety in the control of nasal and non-nasal--including ocular--symptoms of AR. This randomized-controlled trial is the first to evaluate the effects of continuous oral desloratadine treatment on ocular symptoms after conjunctival allergen challenge. To evaluate the impact of administering oral desloratadine 5 mg daily for 7 days on ocular symptoms in conjunctival allergen-challenged subjects. In this crossover study, adults with a history of seasonal AC and a minimal threshold response to allergen challenge were randomized to receive desloratadine 5 mg daily (n=20) or placebo (n=21) for 7 days after which they underwent a second ocular allergen challenge. After a 2-week washout period, subjects crossed over to the other treatment. The primary efficacy parameter was the intra-subject difference from baseline at end-point in the post-challenge mean composite ocular redness score (the sum of redness scores in ciliary, conjunctival, or episcleral vessel beds). Secondary efficacy parameters included the intra-subject and inter-subject differences in individual symptom scores for ciliary, conjunctival, or episcleral redness; pruritus; chemosis; eyelid swelling; and tearing. The mean composite ocular redness score was reduced at 10, 15, and 20 min post-challenge with desloratadine treatment compared with placebo, though these differences were not statistically significant (P=NS). Desloratadine was significantly more effective than placebo in preventing post-challenge ocular pruritus (P<0.001). Significant improvements post-challenge were also seen in ciliary and episcleral redness, chemosis, eyelid swelling, and tearing (P<0.05 vs. placebo for all comparisons). Desloratadine was well tolerated. Treatment with desloratadine 5 mg daily for 7 days reduced allergic ocular symptoms following allergen challenge.

Risk factors for coronary, aortic arch and carotid calcification; The Rotterdam Study

This study was performed to examine the association of cardiovascular risk factors with calcification in the coronary arteries, aortic arch and carotid arteries, assessed by multislice computed tomography (MSCT). This study was embedded in the Rotterdam Study, a population-based study in subjects aged 55 years and over. From October 2003 until December 2004, subjects were invited to undergo a MSCT scan. Coronary, aortic arch and carotid calcification were quantified according to the Agatston score. Analyses were performed in the first 1003 subjects. Age and current smoking were the strongest independent risk factors for arterial calcification. The odds ratio (OR) for age in women, irrespective of the vessel bed, was 1.1 (P<0.001) and in men it was 1.2 with aortic arch and 1.1 with carotid calcification (both P<0.001). Current smoking was associated with aortic arch calcification with an OR of 3.5 in women and of 4.7 in men (both P<0.001); and with carotid calcification with an OR of 2.1 in women (P<0.05) and of 4.1 in men (P<0.01). Hypertension, hypercholesterolemia and diabetes were also independently related to calcification, although not consistent across all vessel beds and for men and women. Obesity tended to be inversely related to arterial calcification in women, whereas low high-density lipoprotein-cholesterol showed no relation with arterial calcification. In conclusion, although associations were not completely consistent across the different vessel beds and for men and women, our results indicate that generally the same risk factors are present for atherosclerosis in the coronary, aortic arch and carotid circulation.

Molecular regulation of tumor angiogenesis and perfusion via redox signaling.

Angiogenesis is one of several processes that form new blood vessels in higher animals, but it has received the most research attention and popular interest due to its important roles in cancer and wound repair. During early embryogenesis, the first capillary networks form by a process known as vasculogenesis. Cells in the mesoderm differentiate into vascular endothelial cells and spontaneously connect to form a network of tubes known as a vascular plexus15. In contrast to angiogenesis, embryonic vasculogenesis occurs in the absence of blood flow. This primitive vascular network connects to primitive arteries and veins in the embryo, which establishes blood flow in the developing tissue. The directional flow is one signal that can promote differentiation of the vascular plexus into a hierarchical network of arteries, arterioles, capillaries, venules, and veins16. This differentiation process is known as arteriogenesis. Arteriogenesis is also directed by growth factors released from growing nerves in the embryo, which results in the parallel organization of blood vessels and nerved noted by early anatomical studies17. During later development and in adult tissues, angiogenesis plays a major role in new blood vessel formation. Angiogenesis is defined as the formation of new blood vessels from an existing perfused vessel bed. This occurs by sprouting of endothelial cells in the vessel wall, either arterial or venous vessels depending on the soluble factors present18,19, which degrade and invade through the underlying basement membrane barrier and then further invade through the underlying extracellular matrix. As the leading cell moves forward, following endothelial cells proliferate and differentiate to form a luminal space. The leading cell eventually finds another vessel, with which it fuses to establish a patent perfused vessel. Further cycles of this process accompanied by arteriogenesis produces a mature vascular network. In addition to endothelial cells, mature blood vessels require supporting smooth muscle cells. During development, these can be recruited from mesenchymal stem cells or from bone-marrow-derived cells. Arterial vessels develop a thick layer of well organized vascular smooth muscle cells (VSMC) to accommodate the greater hydrostatic pressure in the arterial vasculature. These arterial smooth muscle cells, as will be discussed in greater detail below, also play an important role in adjusting blood flow to specific tissues in response to changing metabolic needs. Veins also have well organized smooth muscle layers, but thinner than those in arteries. The VSMC in capillaries are known as pericytes. In contrast to large vessels, capillary endothelial tubes are not completely covered by pericytes. Rather, the pericytes play important roles in capillary stability and function by secreting factors that regulate endothelial cell function and through direct contact with the adjacent capillary endothelium20. Due to the positive hydrostatic pressure in perfused vessels, a net flow of water, ions, and small solutes constantly occurs across the vessel wall. This is opposed by an osmotic gradient resulting from the lower macromolecular solute concentration in the interstitial space, but nonetheless, net fluid movement occurs from perfused vessels into the underlying tissue. To maintain a constant blood volume, higher animals have a second vascular network, the lymphatics, that return this fluid to the cardiovascular system21. Lymphatics are a blind ended tree of specialized vascular cells, which form by a process known as lymphangiogenesis. It has recently become clear that angiogenesis is not the only mechanism responsible for neovascularization of tumors and wounds in the adult22. In adult tissues, vasculogenesis is mediated by recruitment of circulating endothelial precursor cells that differentiate from hematopoietic stem cells in the bone marrow. These along with specialized monocytic stem cells cooperate to form new vessels at sites of injury and in some cancers. The relative contribution of angiogenesis versus vasculogenesis to tumor neovascularization is currently being actively debated, but it is clear that some tumors depend significantly on bone marrow precursor recruitment, whereas this plays a minimal role in others23,24. Likewise, the role of lymphangiogenesis in tumor growth appears to be quite variable, with a subset of tumors being highly dependent on this process25. This review focuses on the role of redox signaling in angiogenesis and angiogenesis inhibition, but the reader should remain aware that some proangiogenic factors can stimulate vasculogenesis, lymphangiogenesis, and arteriogenesis as well as angiogenesis. Correspondingly, angiogenesis inhibitors can often inhibit more than one of these processes. Therefore, the redox signaling pathways discussed here have been initially defined and are best understood in the context of angiogenesis, but their true function may be more general.

Stylostome formation in trombiculid mites (Acariformes: Trombiculidae)

Stylostomes of the trombiculid mite larvae Neotrombicula pomeranzevi (Schluger), Hirsutiella zachvatkini (Schluger), Miyatrombicula esoensis (Sasa and Ogata) and Euschoengastia rotundata (Schluger) (Acariformes: Trombiculidae), formed in the host skin during feeding of the parasites on their natural hosts (voles) were studied histologically and histochemically. A stylostome is a variously shaped tube formed of solidified mite saliva that extends from the mouthparts of the parasite through the epidermis into the dermis of the host, and allows the mite to obtain its liquid food. The first step of stylostome formation is deposition of an eosinophilic cone, to which the larva's chelicerae are glued. Organization of the stylostome depends on the mite species, and its walls may show weakly expressed longitudinal or transverse stratification. Histochemically, the stylostome is composed of complex glycoprotein with varying tinctorial properties through the width or the length of the stylostome's walls. Beneath the distal end of the stylostome, irrespectively of its localization either in the epidermis or in the dermis of the host, a feeding cavity is formed as a result of the action of the hydrolytic components of the mite's saliva forced through the stylostome into the wound. An inflammatory dermal reaction of moderate intensity is evolved during larval feeding and stylostome formation. It is manifested by the infiltration of the foci with neutrophiles, lymphocytes and macrophages and by dilation of capillaries of the terminal vessel bed and filling them by erythrocytes and other blood elements. Around the stylostome, necrosis of the epidermal cells occurs, leucocytes come to the damaged area and fuse with the necrotic epidermal cells, leading to the formation of the large scabs on the surface of the host's skin. In the case of E. rotundata, single capsules having a terminal opening and containing feeding larva are formed on the abdomen of the hosts. The walls of the capsules are composed of the mite's saliva flowing upon the surface of the host's skin. At the bottom of the capsule, a stylostome perforating the epidermis is also present.

Role of c‐myc in coronary vascular development and pathology

The formation and patterning of the coronary vasculature is critical to development and pathology in the heart. During cardiac pathology and physiological growth, coordinated interactions between growth of the organ and formation of the vascular bed are present. Studies from our lab have found that c‐myc is a main regulator of the angiogenic network. Despite the importance of c‐myc in the regulation of the angiogenic cascade, little has been done to explore the role of c‐myc in the formation of the coronary vasculature. In this study we utilized c‐myc+/− mice to examine the effects of diminished c‐Myc on the formation of the vascular bed, vascular patterning, intercapillary space and cardiac function. We observed that c‐myc+/− hearts had decreased cardiac output, diminished vessel bed formation and increased innercapillary space. However, an increase in fractal values suggests an increase in vessel patterning. To recover the effects of c‐myc happloinsufficiencies we crossed c‐myc+/− to the APCmin/+ mouse model, a model in which c‐Myc is increased via β‐catenin stabilization, to make compound APCMIN/+ c‐myc+/− mice. These mice were observed to have recovered the cardiac deficiencies and vessel bed attenuation observed in the c‐myc+/− mouse. However these vessel beds were found to more tortuous and leaky. Together these data highlight the importance of c‐Myc levels in cardiac function and vascular formation.

Examination of Stent Deformation and Gap Formation after Complex Stenting of Left Main Coronary Artery Bifurcations Using Microfocus Computed Tomography

Fluoroscopy and intravascular ultrasound (IVUS) lack sufficient resolution for assessing the results of complex stenting in true bifurcation lesions. After diverse bifurcation stenting at the left main coronary artery (LM) bifurcation model, the results were examined using microfocus computed tomography (MFCT). The strut distribution of three kinds of stents deployed on a straight vessel segment was investigated. Classical crush, double kissing (DK)-double crush, and culotte stenting were performed on a three-dimensional (3D) LM model. The results were assessed using cross-sectional, longitudinal, and 3D reconstruction views of MFCT. Nonuniform strut distribution was observed in a corrugated stent design deployed on a straight vessel segment. Following classical crush stenting, a relatively large gap at the nonmyocardial site was observed in the corrugated stents. When the guidewire recrossed outside the ostium of the crushed side branch stent, kissing balloon inflation caused further crushing of the stent at the more distal segment. The dilated strut rose up from the main vessel bed after the first kissing balloon inflation in DK crush stenting; the advantage of DK would be cancelled after main vessel stenting due to recrushing the raised strut. The culotte stenting with closed-cell stents showed the restriction of the expansion at the branch ostium when it was dilated with a 3.5-mm balloon. The culotte stenting with open-cell-based stents showed a good stent apposition except for a tiny gap and small metallic carina at the distal bifurcation. MFCT analysis in the 3D phantom model is useful to assess the structural deformation of the stents and gap on vessel wall coverage after complex stenting at the LM bifurcation.

Retention of Nanoparticles-Labeled Bone Marrow Mononuclear Cells in the Isolated Ex Vivo Perfused Heart After Myocardial Infarction in Animal Model

Cell therapy of myocardial infarction (MI) is under clinical investigation, yet little is known about its underlying mechanism of function. Our aims were to induce a sub-lethal myocardial infarction in a rabbit, to evaluate the abilities of labeled bone marrow mononuclear cells to migrate from the vessel bed into extracellular space of the myocardium, and to evaluate the short-term distribution of cells in the damaged left ventricle. Sub-lethal myocardial infarction was induced in rabbits by ligation of the left coronary vessel branch (in vivo). The Langendorff heart perfusion model (ex vivo) was used in the next phase. The hearts subjected to MI induction were divided into 3 groups (P1-P3), and hearts without MI formed a control group (C). Nanoparticles-labeled bone marrow mononuclear cells were injected into coronary arteries via the aorta. Perfusion after application lasted 2 minutes in the P1 group, 10 minutes in the P2 and C groups, and 25 minutes in the P3 group. The myocardium of the left ventricle was examined histologically, and the numbers of labeled cells in vessels, myocardium, and combined were determined. The numbers of detected cells in the P1 and C groups were significantly lower than in the P2 and P3 groups. In the P2 and P3 groups, the numbers of cells found distally from the ligation were significantly higher than proximally from the ligation site. Bone marrow mononuclear cells labeled with iron oxide nanoparticles proved the ability to migrate in the myocardium interstitium with significantly higher affinity for the tissue damaged by infarction.

Abstract 683: Regression of Plaque Volume in One Arterial Bed is not Necessarily Associated with Similar Changes in Other Vessels

Background: Population-based studies have shown good correlation between severity of atherosclerotic disease in one arterial bed and involvement of other vessels. However, in patients with coronary artery disease (CAD), it remains unclear whether atherosclerotic plaque in an artery might regress or progress in parallel with other vessels. Accordingly, the present study was performed in patients with CAD to compare changes in plaque volume (PV) between the left main (LMT) and right coronary arteries (RCA), thoracic descending aorta (TDA) and common carotid artery (CCA), and to clarify clinical factors and biomarkers which might affect changes in PV in each artery. Methods: Using 64-multislice computed tomography, PVs in each artery were determined before and after 2.0-year follow-up period in 52 patients with CAD (67.4±9.9yo). Based on our previous study using ultrasound, CCA-PV was determined at windows of 90–240HU and TDA-PV determined manually. Coronary soft plaque was determined at windows of 0–75HU. Plasma levels of hsCRP, matrix metalloproteinase (MMP)-9 and urinary 8-iso-prostaglandin F2 α (PGF) were determined at baseline. Results: At baseline, PVs of TDA were correlated with CCA-PV (r=0.38, p&lt;0.02), but PVs of other arteries did not correlate to each other. Two-year later, PVs of LMT, RCA, TDA, and CCA were reduced in 41, 62, 27, and 39% of patients, respectively. Changes in LMT-PV were weakly related with those of TDA-PV (r=0.37, p=0.02) and RCA-PV (r=0.31, p=0.08), but there were no relation between other arteries. The multivariate analysis revealed that treatment with statin and low LDL-cholesterol (C, &lt;100mg/dl) were independent variables regarding a reduction in DTA-PV, but, in LMT, only low LDL-C was independent variable. However, there were no independent variables in RCA or CCA. The ratio of soft PV to total PV was similar between LMT (45.2±7.1%) and RCA (45.7±4.9%) at baseline and was unchanged in the follow-up study. None of hsCRP, MMP-9 or PGF levels was related with PVs of any arteries at baseline and with changes in PVs. Conclusions: Regression of PV in one arterial bed dose not necessarily allow us to predict atherosclerotic changes in the other vessels. Major factors which affect changes in PV may not be homogeneous between arteries.

Vascular endothelial growth factor and diabetic complications

Intraocular delivery of anti-vascular endothelial growth factor (VEGF) therapies is now used widely to treat age-related macular degeneration, and is currently undergoing evaluation in clinical trials for treatment of diabetic retinopathy. An important aspect of anti-VEGF treatment is that while the agents are injected into the vitreous cavity, they may be absorbed systemically, thus potentially affecting systemic VEGF levels. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and the soluble form of VEGF-R1 are key to angiogenesis, vasculogenesis, neurogenesis and hemodynamics. These cellular processes are regulated by complicated negative and positive feedback loops, many of which are disrupted and altered in diabetes. The VEGF protein, mRNA, as well as the actual VEGF receptor levels, appear to be impaired in diabetes in microvascular and macrovascular vessel beds. What is not clear is the exact role and influence that these levels have on an organ's function. In some organ systems, elevated VEGF levels act as a pathologic angiogenic stimulus (i.e., ocular neovascularization) whereas in others, low levels of VEGF activity leads to pathology (i.e., cardiomyopathy, wound healing and peripheral neuropathy). Diabetic patients have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Certain intraocular anti-VEGF treatments could therefore have an adverse effect in this population by possibly affecting circulating and organ-specific VEGF and VEGF receptor levels.

Commentaries on Viewpoint: The human cutaneous circulation as a model of generalized microvascular function

Commentaries on Viewpoint: The human cutaneous circulation as a model of generalized microvascular function

Imaging techniques for diagnosing a giant coronary artery fistula

A 72-year-old man presented with new onset heart failure. Chest radiography showed marked cardiomegaly and a dense structure contiguous with the left heart border (Fig. 1). Transthoracic echocardiography was unremarkable because of poor echogenicity. Transesophageal echocardiography (TEE) revealed a giant aneurysm located at the posterior side of the left ventricle, near the mitral annulus (Fig. 2). The enlarged circumflex artery flowed towards the left atrial appendage and fed the giant aneurysm. A provisional diagnosis of coronary fistula was made. Coronary angiography (Fig. 3) unequivocally established the diagnosis of a left coronary fistula. However, TEE and coronary angiography failed to determine the drainage site for the fistula. To trace the drainage accurately, computed tomography (CT) angiography was performed, and showed a partially thrombosed giant aneurysm (14 x 9 cm in diameter), fed by the circumflex coronary artery. The site of drainage appeared to be the main coronary vein (Figs. 4 et 5). Taking into consideration the size of the aneurysm and the heart failure, the patient was referred for surgery. The aneurysm was resected and the circumflex artery ligated, without coronary bypass because of the small size of the vessel bed (Figs. 6 et 7). The patient's postoperative course was unremarkable.

The Salvaged Area at Risk in Reperfused Acute Myocardial Infarction as Visualized by Cardiovascular Magnetic Resonance

We aimed to characterize the tissue changes within the perfusion bed of infarct-related vessels in patients with acutely reperfused myocardial infarction (MI) using cardiovascular magnetic resonance (CMR). Even in successful early revascularization, intermittent coronary artery occlusion affects the entire perfusion bed, also referred to as the area at risk. The extent of the salvaged area at risk contains prognostic information and may serve as a therapeutic target. Cardiovascular magnetic resonance can visualize the area at risk; yet, clinical data have been lacking. We studied 92 patients with acute MI and successful reperfusion 3 +/- 3 days after the event and 18 healthy control subjects. Breath-hold T2-weighted and contrast-enhanced ("late enhancement") CMR were used to visualize the reversible and the irreversible myocardial injury, respectively. All reperfused infarcts consistently revealed a pattern with both reversibly and irreversibly injured tissue. In contrast to the infarcted area, reversible damage was always transmural, exceeding the infarct in its maximal extent by 16 +/- 11% (absolute difference of the area of maximal infarct expansion 38 +/- 15% vs. 22 +/- 10%; p < 0.0001). None of the controls had significant T2 signal intensity abnormalities. In patients with reperfused MI, CMR visualizes both reversible and irreversible injury. This allows for quantifying the extent of the salvaged area after revascularization as an important parameter for clinical decision-making and research.

Pharmacologic Strategies for Combating the Inflammatory Response

The “systemic inflammatory response” is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial—or promiscuous—pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.

C-reactive protein is related to extent and progression of coronary and extra-coronary atherosclerosis; results from the Rotterdam study

Aims Although prospective studies have unequivocally shown that C-reactive protein (CRP) is an independent predictor of future cardiovascular events, studies on the association between CRP and atherosclerosis have provided inconsistent results. We investigated the association of CRP with extent and progression of atherosclerosis in multiple vessel beds in a large, population-based cohort study. Methods In the Rotterdam Study, standardized measurements of coronary and extra-coronary atherosclerosis were performed in 1962 persons and 6582 persons, respectively. Progression of extra-coronary atherosclerosis during a mean follow-up period of 6.4 years was assessed in 3757 persons. Results Independent and graded associations were found of CRP with the number of carotid plaques and carotid plaque progression ((OR 1.72; 95% CI 1.14–2.59) for severe progression in participants with CRP > 3 mg/dl versus participants with CRP < 1 mg/dl). Similarly, CRP was independently and graded related to ankle-brachial-index (ABI) and worsening ABI over the years ((OR 1.99; 95% CI 1.37–2.88) for severe progression in participants with CRP > 3 mg/dl versus participants with CRP < 1 mg/dl). Although CRP was independently related to the highest level of carotid intima-media thickness (IMT), the association with change in IMT was not significant. Furthermore, there was an independent, graded relation between CRP and aortic calcification, but no independent association was observed with progression of aortic calcification, nor with the amount of coronary calcification. Conclusion In this population-based study, independent and graded associations were present of CRP with extent and progression of carotid plaques and ABI, while associations with carotid IMT and aortic and coronary calcification were less pronounced.

Radiogenic Lymphangiogenesis in the Skin

The time course of microvascular changes in the environment of irradiated tumors was studied in a standardized human protocol. Eighty skin biopsies from 40 patients with previously treated primary breast cancer were taken from irradiated skin and corresponding contralateral unirradiated control areas 2 to 8 weeks, 11 to 14 months, or 17+ months after radiotherapy (skin equivalent dose 30 to 40 Gy). Twenty-two biopsies of 11 melanoma patients who had undergone lymph node dissection were used for unirradiated control. We found an increase of total podoplanin(+) lymphatic microvessel density resulting mainly from a duplication of the density of smallest lymphatic vessels (diameter <10 microm) in the samples taken 1 year after radiation. Our findings implicate radiogenic lymphangiogenesis during the 1st year after therapy. The numbers of CD68(+) and vascular endothelial growth factor-C(+) cells were highly elevated in irradiated skin in the samples taken 2 to 8 weeks after radiotherapy. Thus, our results indicate that vascular endothelial growth factor-C expression by invading macrophages could be a pathogenetic route of induction of radiogenic lymphangiogenesis.

Extensive Medium-Vessel Vasculitis With SLE

Systemic lupus erythematosus (SLE) is a multisystem disease of autoimmune origin. Vasculitis is often seen with SLE, but is usually limited to small vessels alone. The primary pathology in SLE-related vasculitis is leukocytoclastic vasculitis. Medium- and large-vessel vasculitis in association with SLE is distinctly uncommon and is limited to occasional case reports only. In addition, reports of medium-vessel vasculitis with SLE generally describe involvement of a single vessel bed. We report a rare case of extensive vasculitis involving medium-sized vessels in a patient with SLE. Our patient presented with classic signs and symptoms of SLE and satisfied a majority of the American College of Rheumatology criteria for SLE. She also had toe gangrene at presentation and developed paraplegia during the hospital stay. Radiologic studies showed evidence of diffuse medium-sized vessel vasculitis. The patient was treated with monthly pulse cyclophosphamide and high-dose prednisolone. Follow-up showed no new features of vasculitis and improvement in the signs and symptoms of SLE. Her paraplegia showed no response to treatment. This case stresses that medium-sized vessel occlusion anywhere in the body can occasionally occur due to vasculitis in a patient with SLE.