Intimal Smooth Muscle Cell Proliferation Research Articles

Fibulin-1 promotes intimal hyperplasia after venous stent implantation through ACE mediated angiotensin II signaling

ObjectiveStent intimal hyperplasia leads to in stent restenosis and thrombosis. This study determined whether Fibulin-1 activity in smooth muscle cells (SMCs) contributes to stent restenosis or thrombosis. MethodsStent implantation was conducted in a pig model. Target vessel samples were stained and analyzed by protein mass spectrometry. Cell experiments and Fibulin-1 SMC specific knockout mice (Fbln1SMKO) were used to investigate the mechanism of Fibulin-1 induced SMC proliferation and thrombosis. ResultsSMC proliferation and phenotypic transition are the main pathological changes of intimal hyperplasia in venous stents. Protein mass spectrometry analysis revealed a total of 67 upregulated proteins and 39 downregulated proteins in intimal hyperplasia after stent implantation compared with normal iliac vein tissues. Among them, Fibulin-1 ranked among the top proteins altered. Fibulin-1 overexpressing human SMCs (Fibulin-1-hSMCs) showed increased migration and phenotypic switching from contractile to secretory type and Fibulin-1 inhibition decreased the activity of SMCs. Mechanistically, Fibulin-1-hSMCs displayed increased levels of angiotensin converting enzyme (ACE) expression and angiotensin II signaling. Inhibition of ACE or angiotensin II signaling alleviated the migration of Fibulin-1-hSMCs. Using Fibulin-1 SMC specific knockout mice (Fbln1SMKO) and venous thrombosis model, we demonstrated that Fibulin-1 deletion attenuated intimal SMCs proliferation and thrombosis. Further, Fibulin-1 concentration was high in iliac vein compression syndrome (IVCS) patients treated with stent and was an independent predictor of venous insufficiency. ConclusionsFibulin-1 promotes SMC proliferation partially through ACE secretion and angiotensin II signaling after stent implantation. Fibulin-1 plays a role in venous insufficiency syndrome, implicating the protein in the detection and treatment of IVCS.

Abstract 17441: Non-Invasive Quantification of Peripheral Angioplasty-Induced Vascular Inflammation in a Porcine Model Using PET/CT Imaging

Background: Similarities in peripheral vascular anatomy between swine and humans make this animal an ideal model for evaluating the effects of lower extremity angioplasty procedures commonly performed to improve limb blood flow in peripheral artery disease (PAD). Hypothesis: We hypothesized that PET/CT imaging would provide a non-invasive strategy for quantifying the inflammatory response to balloon overdilation injury in a swine model of peripheral angioplasty. Methods: Five Yorkshire pigs (weight = 25 kg) underwent overdilation of the right femoral artery. A balloon catheter (7 mm x 40 mm) was introduced via the carotid artery and guided to the femoral artery under fluoroscopy. The balloon was then inflated to a pressure 1.5 times greater the recommended nominal pressure to induce arterial injury. 18 F-fluorodeoxyglucose (FDG) PET/CT imaging was performed 14 days after angioplasty to quantify in vivo inflammation in the injured and control femoral arteries, which was expressed as the maximum standardized uptake value (SUV max ). Pigs were euthanized 14 days post-angioplasty and arteries were harvested and sectioned for gamma counting ( 18 F-FDG uptake), and stained with hematoxylin and eosin histology (H&E), Masson’s trichrome, and alpha-smooth muscle actin (α-SMA) for evaluation of intimal remodeling and smooth muscle cell proliferation. Results: 18 F-FDG PET/CT imaging quantified a significant increase in inflammation for the injured versus control femoral artery 14 days post-angioplasty (p=0.04). Gamma counting confirmed a significant increase in 18 F-FDG uptake in the injured artery (p=0.02). H&E revealed a significant increase in intimal thickening in the injured artery (p=0.03). α-SMA expression was also significantly increased in the injured versus control femoral artery (p=0.01), demonstrating an increase in smooth muscle cell proliferation. Conclusions: 18 F-FDG PET/CT quantifies arterial inflammation resulting from overdilation injury that is associated with intimal remodeling and smooth muscle cell proliferation. PET/CT imaging may provide a non-invasive strategy for in vivo testing of the efficacy of emerging drug-coated endovascular peripheral devices.

Inhibitory effect of cilostazol on intimal hyperplasia and smooth muscle cell proliferation in a rabbit carotid artery anastomosis model

Objectives: This study aims to investigate the effect of cilostazol on intimal hyperplasia and smooth muscle cell proliferation in a rabbit carotid artery anastomosis model. Materials and methods: A total of 16 New Zealand male rabbits weighing 2 to 3 kg were used in this study. The rabbits were divided into two groups with eight in each group as Group A and Group B. A vertical neck incision was made in an appropriate position for all group rabbits and the right carotid artery was dissected. The same artery was transected and anastomosis using 8/0 polypropylene was performed with a continuous anastomosis technique. Group A was assigned as the control group and no medication was given. Cilostazol was administrated to Group B at a dose of 25 mg/kg twice a day per oral for 21 days. At the end of Day 21, the anastomosis segments of the right carotid artery and contralateral carotid artery of all rabbits were sent to the histology laboratory for analysis. The lumen diameter, lumen area, intimal area, medial area, and intima/media area ratio were estimated. Results: In the serial sections, the mean lumen diameter of Group B was found to be significantly higher than Group A (p=0.001). The lumen area of Group B was significantly higher than Group A (p=0.001). The section series were evaluated and the area of the intima of Group B was significantly lower than Group A (p=0.001). The medial area of Group B was significantly larger than Group A (p=0.001). The intima/media area ratio was significantly higher in Group A (p=0.001). Conclusion: Cilostazol may be useful for preventing intimal hyperplasia and smooth muscle cell proliferation after vascular surgery.

Necrotizing plasma cell-rich aortitis and sudden cardiac death: Late sequelae of COVID-19?

The ongoing epidemic caused by the coronavirus SARS-CoV-2 is characterized by a variety of pathologic processes within the syndrome of COVID-19. Usually beginning as an upper respiratory infection with potential progression to a pneumonitis, many cases of COVID-19 that show minimal signs or symptoms initially may develop adverse systemic sequelae later, such as widespread thrombo-embolic phenomena, systemic inflammatory disorders (especially in children), or vasculitis. Here, we present a patient who suffered a sudden cardiac death following persistent SARS-CoV-2 viral positivity for four-and-one-half months after a mild clinical viral course. At routine autopsy, a remarkable plasma cell-rich necrotizing aortitis was uncovered. The aortic intima displayed diffuse, circumferential ongoing chronic intimal edema, inflammation, and neo-vascularization. The plasma cell-rich inflammatory process also involved the origin of the left main coronary artery (LM) causing a coronary arteritis accompanied by subacute, stenosing intimal vascular smooth muscle cell (VSMC) proliferation resulting in acute myocardial necrosis as a cause of death. A similar vasculitis and plaque were noted during the routine autopsy at the ostium of the celiac artery; vasculitis was not found systemically or in smaller caliber vessels. Through a variety of techniques including extensive histopathologic and immunohistochemical characterization, immunostaining localization of viral antigen, and transmission electron microscopy we present highly suggestive evidence that this unique necrotizing, plasma cell-rich aortitis is a rare sequela of COVID-19.

ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation.

SummaryVascular smooth muscle cell (VSMC) proliferation promotes intimal hyperplasia (IH) in occluding vascular diseases. Here we identified a positive role of ALDH1A3 (an aldehyde dehydrogenase) in this pro-IH process. The expression of ALDH1A3, but not that of 18 other isoforms of the ALDH family, was substantially increased in cytokine-stimulated VSMCs. PDGF(BB) stimulated VSMC total ALDH activity and proliferation, whereas ALDH1A3 silencing abolished this effect. ALDH1A3 silencing also diminished the expression of two matricellular proteins (TNC1 and ESM1), revealing a previously unrecognized ALDH1A3 function. Loss-of-function experiments demonstrated that TNC1 and ESM1 mediated ALDH1A3's pro-proliferative function via activation of AKT/mTOR and/or MEK/ERK pathways. Furthermore, ALDH inhibition with disulfiram blocked VSMC proliferation/migration in vitro and decreased TNC1 and ESM1 and IH in angioplasty-injured rat carotid arteries. Thus, ALDH1A3 promotes VSMC proliferation at least partially through TNC1/ESM1 upregulation; dampening excessive ALDH1A3 activity represents a potential approach to IH mitigation.

[Reaction of connective tissue of arterial and venous walls to implantation of synthetic and biological grafts].

30% of patients in the remote period appear to develop restenosis of the anastomoses formed during reconstructive-restorative operations on vessels. Two major causes of restenosis have been determined: intimal hyperplasia and smooth muscle cell proliferation. The reaction of connective-tissue elements of vascular walls in response to implantation of grafts remains unstudied. The study was undertaken to examine the reaction of connective tissue of the arterial and venous walls to implantation of synthetic and biological grafts. We analysed the results of an experimental study performed on a total of 60 rabbits divided into 4 groups each consisting of 15 animals: in the first 2 groups we examined tissue reaction to implantation of synthetic and biological grafts on the wall of an artery and in the remaining 2 groups - on the wall of a vein. The synthetic grafts were made of polytetrafluoroethylene, with the biological ones made of bovine internal thoracic arteries. The portions of the vessels along with the implanted grafts were subjected to histological examination on postoperative days 14, 21 and 30. The specimens were studied by means of light microscopy after haematoxylin-eosin staining. We also carried out a morphometric study consisting in determining the quantitative ratio of the cellular composition of connective tissue. After implantation on the arterial wall, the connective-tissue capsule under the synthetic prosthesis was 1.8 times thicker than under the biological one, with predominance of the cellular component over fibrous one, which deformed the zone of implantation. Under the biological prosthesis, the capsule on the arterial wall was presented by fibrous structures with no deformation of the zone of implantation. The reparative reaction of the venous wall to implantation of the synthetic prosthesis was represented by a thin fibrous connective-tissue capsule. The reaction of the venous wall to the biological transplant was at all terms of the experiment characterised by significant inflammatory alterations with granulomatosis and immunomorphological shifts with formation of lymphoid follicles on the border with the transplant. Implantation of the synthetic polytetrafluoroethylene prosthesis on the arterial wall induced a hyperplastic reaction of the elements of connective tissue, and a normoplasic one on the venous wall. Implantation of the biological prosthesis on the arterial wall did not induce proliferation of connective-tissue elements, and on the venous wall - granulomatous inflammation.

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts.

BackgroundNintedanib is a small molecule tyrosine kinase inhibitor that blocks the action of the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR) and the fibroblast growth factor receptor. All of these receptors have been shown to be involved in the development of cardiac allograft vasculopathy (CAV) after heart transplantation. We therefore hypothesized that blocking these tyrosine kinase receptors with nintedanib could prevent CAV.MethodsCBA/JRj (H2k) mice underwent an abdominal aortic transplantation with a graft derived from fully allogeneic C57BL/6JRj (H2b) mice. Nintedanib was given daily from the first day after transplantation until harvest on day 14 for polymerase chain reaction analysis of intragraft cytokine expression or harvest on day 30 for histological analysis of the graft.ResultsNintedanib treatment resulted in significantly reduced neointima formation in the aortic graft compared with untreated control allografts. Interestingly, the immigration of smooth muscle cells into the neointima was markedly reduced while graft infiltrating macrophages and T cells were not altered in nintedanib-treated animals. The expression of the growth factor PDGF was significantly reduced in the nintedanib group going along with a distinctly reduced expression of the corresponding receptors PDGFR α and -β.ConclusionsTreatment with nintedanib caused a significant reduction of CAV development after aortic transplantation in mice. We hypothesize the attenuated neointima formation in nintedanib-treated animals to be mediated by a direct inhibition of intimal smooth muscle cell proliferation via reduced expression of PDGF and the appropriate receptors PDGFR α + β.

Effects of rivaroxaban on intimal hyperplasia and smooth muscle cell proliferation at the carotid artery anastomosis site in rabbits.

Objective:This study aimed to assess the effect of new generation oral, direct factor Xa inhibitor rivaroxaban on intimal hyperplasia and smooth muscle cell proliferation at the carotid artery anastomosis site of rabbits.Methods:In total, 14 New Zealand male rabbits weighing 3–3.5 kg were randomized into two groups. Group A (7 rabbits) served as the control group and received no medication. Rivaroxaban was perorally administered to group B (7 rabbits) mg/kg/day for 28 days. Following anesthesia induction, carotid arteries were dissected through a right neck incision. following heparinization at 100 IU/kg, vertical full thickness arteriotomy was performed, then was repaired continuously with 8-0 polypropylene. At day 28, all rabbits were sacrificed and the anastomosed carotid artery segments were analyzed using light microcopy. Hematoxylin–eosin and Masson’s trichrome stained images were analyzed using a digital image analysis program, and lumen diameter, lumen area, intimal and medial thickness, and media areas were measured and results were compared.Results:In the serial sections, the average lumen diameter of group B was higher than that of group A (p=0.001). The lumen areas of group B were also higher than those of group A (p=0.004). The intimal thickness of group B was lower than that of group A (p=0.001). When the section series were evaluated for media thickness, the thickness of group B was lesser than that of group A; the difference was statistically significant (p=0.002).Conclusion:This study may imply a potential midterm benefit of rivaroxaban following arterial anastomosis by reducing intimal proliferation and restenosis.

A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation.

Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity. We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2) donors and BALB/c (H-2) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (quantitative real-time reverse-transcriptase polymerase chain reaction). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. We noted significantly greater intimal hyperplasia in HET versus WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-кB activation, gauged by higher levels of IkBα, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET versus WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFNγ and Granzyme B CD4 T cells and natural killer cells, and lower number of FoxP3 regulatory T cells. A20 haploinsufficiency in allograft recipients did not influence TA. A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic T cells. A20 single nucleotide polymorphisms associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings.

Circulating soluble LR11, a novel marker of smooth muscle cell proliferation, is enhanced after coronary stenting in response to vascular injury

ObjectiveRestenosis after vascular intervention remains a major clinical problem. Circulating LR11 has been shown a novel marker of intimal smooth muscle cell (SMC) proliferation in human and animal studies. The present study was performed to clarify the clinical significance of circulating LR11 in patients with stable angina pectoris after coronary stenting. Methods and resultsWe firstly investigated the circulating sLR11 levels for 28 days after arterial injury in mice, and then assessed time-dependent change in circulating sLR11 level after coronary stenting in a clinical study. Mouse sLR11 levels rapidly increased to 4.0-fold of the control value without cuff placement at postoperative day (POD) 14, and the levels gradually declined to 3.1-fold of the control value until POD 28 in mice. The circulating soluble LR11 levels were measured (before and at 14, 60 and 240 days after coronary stenting in a clinical study of 102 consecutive patients with stable angina pectoris who were treated with percutaneous coronary intervention. Circulating sLR11 levels were significantly increased on days 14 and 60 after the procedure and positively associated with the angiographic late loss index. ConclusionsOur study suggested that circulating sLR11 levels may be a potential marker for angiographic late loss in patients after coronary stenting. Further mechanistic studies are expected to know the clinical significance of sLR11 as a novel marker for intimal SMC.

Repetitive Hypoglycemia Increases Circulating Adrenaline Level with Resultant Worsening of Intimal Thickening After Vascular Injury in Male Goto-Kakizaki Rat Carotid Artery

Hypoglycemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect of hypoglycemic episodes including a surge of sympathetic activity on the progression of neointima formation after vascular injury remains largely unknown. In this study, insulin was injected intraperitoneally into nonobese diabetic Goto-Kakizaki (GK) rats, once every 3 days for 4 weeks after balloon injury of carotid artery to induce hypoglycemia. Then, we evaluated balloon injury-induced neointima formation. Insulin treatment enhanced neointima formation and increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in the carotid artery. Injection of glucose with insulin prevented hypoglycemia and abrogated intimal thickening. Also, bunazosin, an α1 adrenergic receptor antagonist, prevented intimal thickening and accumulation of PCNA-positive cells induced by insulin treatment despite the presence of concomitant hypoglycemia and high adrenaline levels. Incubation of cultured smooth muscle cells with adrenaline resulted in a significant increase in their proliferation and G0/G1 to S phase progression, which was associated with activation of extracellular signal-regulated kinase, enhanced expression of cell cycle regulatory molecules such as cyclin D1, and cyclin E, and phosphorylation of retinoblastoma protein. These adrenaline-induced effects were abrogated by bunazosin. Our data indicated that increased adrenaline induced by repetitive hypoglycemia promotes intimal thickening and smooth muscle cell proliferation after endothelial denudation in GK rats.

Combination of Periaortic Elastase Incubation and Cholesterol-Rich Diet: A Novel Model of Atherosclerosis in Rabbit Abdominal Aorta

Atherosclerosis, the leading cause of most cardiovascular disease, is a progressive multifaceted inflammatory disease characterized by extracellular matrix degradation and extensive remodeling of artery wall. However, its mechanism has not been completely understood, and animal models are useful to study its pathogenetic process. An analysis of literature on the nature of atherosclerosis indicates that focal accumulation of smooth muscle cells (SMCs) into the intima by plasma factors is fundamental to the entire process of plaque growth. In our previous study, vascular SMCs proliferation was obvious in elastase-induced aorta by day 15, which led to intimal hyperplasia and regression of rabbit aneurysm. Model induced by combination of balloon injury and an atherogenic diet in rabbits is the conventional, but most largely used experimental model of atherosclerosis. Since proliferation and accumulation of intimal SMCs are found in elastase-induced aorta, and hypercholesterolemia is usually induced by cholesterol-rich diets in rabbits, a novel atherosclerosis model may be induced by combination periaortic elastase incubation and cholesterol-rich diet.

English

This study aimed to evaluate the inhibitory effect of pentoxifylline, a phosphodiesterase inhibitor on intimal hyperplasia (IH) and vascular smooth muscle cell proliferation in an anastomosis model of rabbit carotid artery (CA). Right CAs of 18 male New Zealand white rabbits were anastomosed under general anesthesia. After the surgical procedure, 18 rabbits were separated into three study groups, 6 in each. Group 1 (control group) did not receive any treatment. Group 2 and 3 were treated with 100 mg/kg/day subcutaneous pentoxifylline for 7 and 21 days, respectively. After 28 days, histopathological assessments and histomorphometric measurements were performed on the CA segments. In the histological sections, IH was less evident in the anastomosed vessel wall in pentoxifylline-treated groups than in Group 1. The mean luminal diameter (LD), luminal area (LA), intimal thickness (IT), and intima/media ratio (IMR) for Group 1 were 472.63 ± 13.28 μm, 301,973.33 ± 12,951.27 μm2, 200,844.67 ± 8,375.38 μm, and 0.52 ± 0.01, respectively. The LD and LA were significantly higher, and the IT and IMR were significantly lower for Group 2 and 3 compared with Group 1 (p 0.05). Subcutaneous pentoxifylline treatment, even for duration of only seven days decreases IH in arterial anastomosis sites in a rabbit CA anastomosis model.   Key words: Pentoxifylline, vascular graft, anastomosis, carotid arteries.

ASSA13-10-2 Efficacy and Safety of Bosentan in Patients with Pulmonary Arterial Hypertension Secondary to Congenital Heart Disease

Background Pulmonary arterial hypertension (PAH) is a major complication of congenital heart disease (CHD), causing increase morbidity and mortality with age. Sustained increase in the pulmonary arterial pressure (PAP) may result in progressive pulmonary vascular remodelling and eventually lead to irreversible changes including extensive intimal injury, obliteration, adventitial fibrosis and smooth muscle cell proliferation. In recent years, insight into the pathogenesis of PAH has resulted in the development of therapeutic strategies for PAH including endothelin receptor antagonists, prostacyclin analogues and phosphodiesterase-5 inhibitors. Endothelin has a key role in the pathobiology of PAH, exerting vasoconstrictor and mitogenic effects by binding to two distinct receptor isoforms in the pulmonary vascular smooth musc-le cells. Bosentan, an orally active dual endothelin receptor antagonist, has been shown to improve exercise capacity, hemodynamics in patients with idiopathic, chronic thromboembolic, and connective tissue disease-associated PAH. However the data of efficacy and safety of bosentan in patients with CHD and PAH is limited. Objective The present study aimed to investigate the efficiency and safety of dual endothelin receptor antagonist bosentan in patients with CHD and severe PAH. Methods Between May 2008 and January 2011, a total of 18 patients with severe PAH secondary to left-to-right shunt CHD were treated with bosentan. All patients underwent cardiac evaluation, including reviewing medical history, physical examination, electrocardiogram and echocardiogram, and cardiac catheterization. The patients with IPAH or PAH secondary to valvular heart diseases, complex CHDs, heart failure (≥NYHA Class III) and other system diseases, and those who had a positive response during acute vasodilator test were excluded from this study. All the patients were treated with bosentan as well as digoxin, diuretics and warfarin for 6 months. Oral bosentan was initiated at 62.5 mg twice daily, increasing after 4 weeks to 125 mg twice daily thereafter in patients weighing > 40 kg and initiated at 31.25 mg twice daily, increasing after 4 weeks to 62.5 mg twice daily in patients weighing ≤40kg. Patients were assessed at 1-month intervals using physical examination, 6-minute walk test, complete blood count and blood biochemistry. Electrocardiogram, X-ray, echocardiogram and right heart catheterization were repeated 6 months after treatment with bosentan. Results There were 6 males and 12 females with age ranging from 9 to 55 (28.7 ± 11.3) years in this series. The basic defects included atrial septal defect (ASD; n = 6), ventricular septal defect (VSD; n = 4) and patent ductus arteriosus (PDA; n = 8). The echocardiogram showed right ventricular diameter (RVD) of 26 ± 8 mm, tricuspid regurgitation speed (VP) of 5.0 ± 0.7 m/s, transtricuspid pressure gradient (PGTV) of 100 ± 26 mmHg, left ventricular end-diastolic diameter (LVEDD) of 37 ± 5mm, left ventricular end-diastolic volume (LVEDV) of 51 ± 21 ml and left ventricular ejection fraction (LVEF) of 0.71 ± 0.06. Right heart catheterization showed oxygen saturation (SaO2) of femoral artery blood of 88.7 ± 5.9%, systolic pulmonary artirial pressure (sPAP) of 115 ± 19 mmHg (1mmHg = 0.133kp), diastolic pulmonary arterial pressure (dPAP) of 63 ± 13 mmHg, mean pulmonary artery pressure (mPAP) of 81 ± 15 mmHg, pulmonary-to-systemic flow (Qp/Qs) ratio of 0.76 ± 0.24 and pulmonary vascular resistance (PVR) of 19.6 ± 7.7 Woods. Six months after treatment with bosentan, echocardiogram showed no significant changes in right ventricular diameter (24 ± 8 mm, P > 0.05), VP (4.7 ± 0.4 m/s, P > 0.05), PGTV (93.3 ± 13.7 mmHg, P > 0.05), LVEDD (39 ± 4 mm, P > 0.05), LVEDV (60 ± 20 ml, P > 0.05), and LVEF (0.72 ± 0.07, P > 0.05). However, 6-minute walk distance (6-MWD) increased from 353 ± 101 to 480 ± 81 m (P 0.05), dPAP (59 ± 14 mmHg, P > 0.05) and mPAP (78 ± 10 mmHg, P > 0.05), the SaO2 of femoral artery blood and Qp/Qs ratio were increased to 91.0 ± 3.2% (P Conclusions Bosentan was well tolerated and effective for improving exercise capacity and hemodynamics in patients with PAH secondary to CHD. Different to IPAH and PAH secondary to other diseases, bosentan therapy did not cause decrease in pulmonary arterial pressure but PVR and increase in Qp/Qs ratio.

Increased circulating soluble LR11 in patients with acute coronary syndrome

BackgroundLR11 (also so called SorLA or SORL1) is a novel marker of intimal smooth muscle cell (SMC) proliferation. Vascular SMCs play important roles in the development of atherosclerosis interacting with macrophages in a vulnerable plaque of patients with acute coronary syndrome (ACS).The present study determines whether soluble LR11 (sLR11) is associated with ACS. MethodsWe studied 100 patients with coronary artery disease (CAD) comprising 50 consecutive patients with acute coronary syndrome (ACS; mean age 62.3±13.0years; male 78.0%) who were successfully treated with percutaneous coronary intervention and 50 age- and sex-matched stable angina pectoris (SAP) patients as control. Concentration of sLR11 was measured by sandwich enzyme-linked immunosorbent assay method. ResultsCirculating sLR11 was significantly increased in patients with ACS compared with SAP (9.88±2.78 vs. 8.18±1.11ng/ml, p<0.01). Multivariate logistic regression analysis indicated that sLR11 was independently associated with ACS (odds ratio (OR), sLR11 quartile increment, 2.18, 95% confidence interval (CI) 1.21–4.19, p<0.01). Among various biomarkers of acute coronary syndrome, hsCRP were significantly correlated with LR11 (r=0.480, p<0.01). ConclusionsThere is a statistical significant association between LR11 and ACS and may be a useful biomarker for the development of acute coronary syndrome.

Internal cerebral veins varix due to midline arteriovenous malformation: how much is the risk of bleeding?

We report a case of 40-year-old sportsman admitted to our department for a generalized seizure associated with bladder and bowel incontinence occurred during exercise. The patient quickly regained consciousness without postcritical deficits. Neurological examination appeared completely normal. A head computer tomography (CT) scan showed a midline arteriovenous malformation (AVM) without the evidence of bleeding (Fig. 1a, b). A digital subtraction angiography revealed a dysplastic nidus fed by branches of bilateral internal–external carotid and vertebrobasilar arteries, and draining both in the superficial and deep venous system, which showed varicose dilatation with Galen’s vein stenosis (Fig. 1c–g). Cerebral varix is defined as an ectasia which doubles vein diameter. It can be due to an arteriovenous shunt and appears more common in patients with direct fistulas, than in cerebral AVM with dysplastic nidi [1]. Differently from those associated with Galen’s vein fistulae, huge intracranial varix associated with cerebral AVMs were seldom reported. Headache, bruit, focal mass effect and hydrocephalus are common presentation symptoms [2]. Intracranial haemorrhage has been instead less often reported at clinical onset [3]. In the most of the cases of giant varix, direct arteriovenous communications in the context of nidus were observed, especially between feeding arteries and the varicose veins [4]. This discrete angiographic finding separate these vascular malformations from the classical and more common AVMs in which an abnormal vascular network is identified between the arterial feeders and draining veins [4]. Venous hypertension with retrograde drainage often results in focal neurological deficits and seizures [1]. Although it is commonly assumed that venous ectasia increases the bleeding risk, varix haemorrhagic presentation has been rarely reported [4]. It is may be due to the progressive thickening of the arterialized veins wall, with intimal proliferation of synthetic smoothmuscle cells and disappearance of the internal elastic lamina, that make arterialized veins not greatly prone to rupture [1, 4]. On the other hand, instead, the presence of venous varix on the draining veins has been recognized as a factor increasing the risk of haemorrhage in dural arteriovenous fistulae [5]. In the case reported here, the presence of multiple feeders causing high flow shunt rate, direct drainage in a cisternal venous system, and an impaired venous outlet due to the Galen’s vein stenosis, may have contributed to the varix formation. Prolonged sporting activity, instead, has not been a factor influencing AVM rupture.

Beyond arterial remodelling: pulmonary venous and cardiac involvement in patients with systemic sclerosis-associated pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) represents a heterogeneous group of disorders characterised by elevated pulmonary vascular resistance and a normal pulmonary artery wedge pressure that occurs in the absence of left heart disease, chronic lung diseases/hypoxia or chronic thromboembolic pulmonary disease 1. Entities within the PAH group share not only similar symptoms and haemodynamic profiles but also a common therapeutic approach 2. Unfortunately, outcome among PAH patients remains poor and a cure for the disease remains elusive 3. One additional, although less well described, feature that favours the distinction of a PAH group is the histomorphological correlate of elevated blood pressures within the pulmonary vasculature. Indeed, PAH that is idiopathic, heritable, or associated with anorexigen exposure, HIV infection, portopulmonary hypertension and connective tissue disease (comprising mostly systemic sclerosis (SSc)-associated PAH (SSc-PAH)) appear to have a similar pulmonary arterial and arteriolar remodelling pattern. Typical PAH lesions consist mainly of widely and uniformly distributed vascular alterations, including intimal fibrosis, and endothelial and smooth muscle cell proliferation, without obvious involvement of the bronchoalveolar architecture. These histological features are markedly different from pulmonary hypertension that arises as a consequence of chronic thromboembolic disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and sarcoidosis, in which vascular occlusion develops as a consequence of emboli, arteriolar rarification, interstitial scarring or obstructing granulomas, respectively. Despite similarities in pathological anatomy, clinical management and outcome among the different forms of PAH, there are, nonetheless, important differences that remain unexplained. In patients with SSc, PAH is a leading cause of mortality that requires intensive medical management. However, therapeutic responses are frequently less favourable compared to other forms of PAH 4–6. SSc-PAH treatment with vasodilators such as continuous intravenous epoprostenol is associated with improvements in exercise capacity and cardiopulmonary haemodynamics. However, therapeutic responses using prostanoid therapy in …

Pathogenesis of primary varicose veins

Valvular incompetence and reflux are common features of primary varicose veins, and have long been thought to be their cause. Recent evidence, however, suggests that changes in the vein wall may precede valvular dysfunction. A literature search was performed using PubMed and Ovid using the keywords 'varicose vein wall changes', 'pathogenesis', 'aetiology' and 'valvular dysfunction'. Articles discussing the pathophysiology of complications of varicose veins, such as ulceration, recurrence, thrombophlebitis and lipodermatosclerosis, were excluded. Positive family history, age, sex and pregnancy are important risk factors for varicose vein formation. Areas of intimal hyperplasia and smooth muscle cell proliferation are often noted in varicose veins, although regions of atrophy are also present. The total elastin content in varicose as opposed to non-varicose veins is reduced; changes in overall collagen content are uncertain. Matrix metalloproteinases (MMPs), including MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, and tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP-3 are upregulated in varicose veins. Activation of the endothelium stimulates the recruitment of leucocytes and the release of growth factors, leading to smooth muscle cell proliferation and migration. Dysregulated apoptosis has also been demonstrated in varicose veins. An understanding of the pathophysiology of varicose veins is important in the identification of potential therapeutic targets and treatment strategies.

Anti–LFA-1 Monotherapy Prevents Neointimal Formation in a Murine Model of Transplant Intimal Hyperplasia

Cardiac allograft vasculopathy (CAV) is the pre-eminent cause of late cardiac allograft failure. It is characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). To date, blockade of the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) has been shown to be effective in preventing TIH in experimental models of transplantation, but only when combined with other immunosuppressants. In this study we explored the impact of monotherapy against LFA-1 in a carotid artery allograft model of TIH. B10A(2R) (H-2(h2)) mice were used as donors and C57BL/6 (H-2(b)) mice used as recipients. The recipients were treated with a monoclonal antibody against LFA-1alpha (M17/4) or isotype-matched control immunoglobulin. Grafts were harvested after 35 days and analyzed by histomorphometry and immunohistochemistry. Blood samples were taken and analyzed by differential cell count and alloantibody levels. We found that treatment with M17/4 resulted in a significant reduction in TIH compared with controls. Immunostaining revealed that LFA-1alpha blockade inhibited CD45+ leukocyte infiltration, prevented intimal smooth muscle cell (SMC) proliferation, and preserved the medial SMC population. Finally, we demonstrated a reduction in the serum alloantibody titer in the group treated with anti-LFA-1alpha when compared with controls. We have demonstrated for the first time that LFA-1alpha blockade on its own can prevent development of TIH in an experimental model. The concept of modulating LFA-1alpha-mediated leukocyte migration and T-cell activation may therefore be of relevance to clinical cardiac transplantation and, as such, represents a potential target for therapeutic intervention against clinical CAV.

Smooth muscle cell proliferation but not neointimal formation is dependent on alloantibody in a murine model of intimal hyperplasia.

Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2(h2)) donor mice and B-cell deficient muMT(-/-) knockout or wild-type C57BL/6 (H-2(b)) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to muMT(-/-) recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent.