Bassam Redwan

Role for Staphylococci in Misguided Thrombus Resolution of Chronic Thromboembolic Pulmonary Hypertension

Objective—Acute pulmonary emboli usually resolve within 6 months. However, in 0.1% to 3.8% of cases thrombus transforms into fibrous masses. If vascular obstruction is severe, the resulting condition is chronic thromboembolic pulmonary hypertension (CTEPH). Patients who carry ventriculo-atrial (VA-) shunts for the treatment of hydrocephalus and report a history of shunt infection are at an increased risk for CTEPH. Because CTEPH lacks traditional plasmatic risk factors for venous thromboembolism, we hypothesized that delayed thrombus resolution rather than abnormal coagulation is important, and that bacterial infection would be important for this misguidance. Methods and Results—Human CTEPH thromboemboli were harvested during pulmonary endarterectomy. The effects of Staphylococcal infection on thrombus organization were examined in a murine model of stagnant-flow venous thrombosis. Staphylococcal DNA, but not RNA, was detected in 6 of 7 thrombi from VA shunt carriers. In the mouse model, staphylococcal infection delayed thrombus resolution in parallel with upregulation of transforming growth factor (TGF) beta and connective tissue growth factor. Conclusions—In the present work, we propose a mechanism of disease demonstrating that infection with Staphylococci enhances fibrotic vascular remodeling after thrombosis, resulting in misguided thrombus resolution. Thrombus infection appears to be a trigger in the evolution of CTEPH.

Defective Angiogenesis Delays Thrombus Resolution A Potential Pathogenetic Mechanism Underlying Chronic Thromboembolic Pulmonary Hypertension

Objective— Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence.nnApproach and Results— Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor.nnConclusions— In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.nn# Significance {#article-title-44}Objective—Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results—Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions—In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.

Splenectomy Is Modifying the Vascular Remodeling of Thrombosis

Background Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis. Methods and Results We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension (CTEPH), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of CTEPH patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte–platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine‐enriched phospholipids specifically inhibited endothelial proliferation and sprouting. Conclusions After splenectomy, an increase in circulating microparticles and negatively charged phospholipids is enhanced by experimental thrombus induction. The initial increase in thrombus volume after splenectomy is due to platelet activation, and the subsequent delay of thrombus resolution is due to inhibition of thrombus angiogenesis. The data illustrate a potential mechanism of disease in CTEPH.

Systemic endothelin receptor blockade in ST-segment elevation acute coronary syndrome protects the microvasculature: a randomised pilot study

AIMSnST-elevation acute coronary syndrome (STE-ACS) is characterised by compromised blood flow at the epicardial and microvascular levels. Endothelin-1 (ET-1) is a mediator of microvascular dysfunction and adverse cardiac remodelling. We hypothesised that administration of an endothelin type A (ETA) receptor antagonist (BQ-123; Clinalfa, Läufelfingen, Switzerland) may protect microvascular function.nnnMETHODS AND RESULTSnIn this proof-of-concept, randomised, double-blind, placebo-controlled trial, patients with posterior-wall STE-ACS (n=57) were randomly assigned to receive intravenous BQ-123 at 400 nmol/minute or placebo over 60 minutes, starting at the onset of primary percutaneous coronary intervention (PCI). Time to myocardial contrast wash-in of the infarcted segment assessed by first-pass perfusion cardiac magnetic resonance imaging was the primary efficacy endpoint. Secondary endpoints included enzymatic infarct size and left ventricular ejection fraction (LVEF). In patients randomised to BQ-123 we observed shorter microvessel perfusion delays six days after PCI (1.8 sec [0.7-3.4] versus 3.3 sec [2.3-5.4] in placebo-treated patients, p=0.005). The treatment group demonstrated smaller enzymatic infarct sizes (p=0.014). All patients were alive at six months, with an LVEF of 63% (58-69) in patients randomised to BQ-123 and 59% (51-66) in placebo-treated patients (p=0.047).nnnCONCLUSIONSnAdministration of an ETA receptor blocker during primary PCI in patients with STE-ACS is safe and may improve tissue-level perfusion and LVEF.

Intraoperative veno-venous extracorporeal lung support in thoracic surgery: a single-centre experience

OBJECTIVESnIntraoperative extracorporeal lung support (ECLS) during thoracic surgical procedures is a modern concept that is gaining increasing acceptance. So far, cardiopulmonary bypass (CPB), veno-arterial extracorporeal membrane oxygenation (v-a-ECMO) or pumpless arterio-venous interventional lung assist (iLA) were utilized for intraoperative support. Only a few case reports have described the use of veno-venous ECMO for intraoperative ECLS. Here, we report our experience with intraoperative ECLS using different veno-venous low-flow and high-flow settings adapted to the individual patient requirements.nnnMETHODSnBetween April 2014 and April 2015, 9 patients underwent pulmonary resections under ECLS. In 6 patients, a twin-port double-lumen cannula was inserted percutaneously into the right femoral vein for low-flow ECLS. In 3 patients, high-flow ECLS was achieved either by femoro-atrial (n = 1) or femoro-jugular cannulation.nnnRESULTSnIndications for ECLS were severely impaired lung function (n = 3), previous pulmonary resections including contralateral pneumonectomy (n = 4), previous single-lung transplantation (sLTX) (n = 1) and extended carinal pneumonectomy (n = 1). Procedures included segmentectomy (n = 3), extended lobectomy with bronchial and vascular anastomoses (n = 1), VATS lobectomy (n = 2), extended left-sided carinal pneumonectomy (n = 1) as well as extended metastasectomy (n = 2). Low-flow ECLS allowed for apnoea up to 45 min in patients with previous pneumonectomy (n = 3) and facilitated protective single-lung ventilation in patients (n = 3) with severely impaired pulmonary function. During trans-sternal carinal pneumonectomy (n = 1), high-flow ECLS achieved by femoro-atrial cannulation allowed for apnoea for 40 min, avoiding cross-field ventilation. In 2 patients requiring extended metastasectomy after previous lobectomy of the contralateral lower lobe (n = 1) or pulmonary metastases in the graft after sLTX for end-stage fibrosis (n = 1), high-flow ECLS by percutaneous femoro-jugular cannulation allowed for extensive metastasectomy under optimal atelectasis of the lung.nnnCONCLUSIONSnFor intraoperative ECLS, different modes may be applied depending on the intended procedures and required mechanical ventilation. In our experience, different settings of veno-venous ECLS provide sufficient partial or complete lung support, avoiding possible complications associated with other forms of extracorporeal support such as CPB or v-a-ECMO.

Peri-interventional endothelin-A receptor blockade improves long-term outcome in patients with ST-elevation acute myocardial infarction

Endothelin (ET)-1 is a pro-fibrotic vasoconstrictive peptide causing microvascular dysfunction and cardiac remodelling after acute ST-elevation myocardial infarction (STEMI). It acts via two distinct receptors, ET-A and ET-B, and is involved in inflammation and atherogenesis. Patients with posterior-wall STEMI were randomly assigned to intravenous BQ-123 at 400 nmol/minute (min) or placebo over 60 min, starting immediately prior to primary percutaneous coronary intervention (n=54). Peripheral blood samples were drawn at baseline as well as after 24 hours and 30 days. Myeloperoxidase (MPO), as a marker of neutrophil activation and matrix metalloproteinase 9 (MMP-9), a marker of extracellular matrix degradation were measured in plasma. Clinical follow-up was conducted by an investigator blinded to treatment allocation over three years. During the median follow-up period of 3.6 years (interquartile range [IQR] 3.3-4.1) we observed a longer event-free survival in patients randomised to receive BQ-123 compared with patients randomised to placebo (mean 4.5 years (95% confidence interval: 3.9-5) versus mean 3 years (2.2-3.7), p=0.031). Patients randomised to ET-A receptor blockade demonstrated a greater reduction of MPO levels from baseline to 24 hours compared to placebo-treated patients (-177 ng/ml (IQR 103-274) vs -108 ng/ml (74-147), p=0.006). In addition, a pronounced drop in MMP-9 levels (-568 ng/ml (44-1157) vs -117 ng/ml (57-561), p=0.018) was observed. There was no significant difference in amino-terminal propetide of pro-collagen type III levels. In conclusion, short-term administration of BQ-123 leads to a reduction in MPO, as well as MMP-9 plasma levels and to a longer event-free survival in patients with STEMI.

Pectus Excavatum and Cardiac Surgery: Simultaneous Correction Advocated

BACKGROUNDnSevere pectus excavatum may be present in combination with cardiac conditions requiring open-heart surgery. The best strategy for this situation has been debated controversially.nnnPATIENTS AND METHODSnIn a retrospective study, we analyzed all our patients undergoing concurrent pectus excavatum correction and open-heart surgery.nnnRESULTSnTen patients aged 9 to 70 years underwent a simultaneous combined surgical procedure between 2001 and 2013. Indications for cardiac surgery were various forms of congenital and acquired heart disease including coronary artery disease with internal thoracic artery grafts and ascending aortic aneurysms. A modified Ravitch procedure was performed for pectus excavatum correction (mean Haller-Index 5.0). Mean operating time was 364 (210-495) minutes and mean duration of cardiopulmonary bypass was 125 (54-222) minutes. All procedures were completed successfully. Postoperatively minor complications were observed in three patients. In-hospital and 30-day mortalities were nil. Good cosmetic and functional results were achieved in all patients.nnnCONCLUSIONSnOur data demonstrate that simultaneous pectus excavatum correction and cardiac surgery is effective and reliable. A combined approach is advocated if candidates for cardiac surgery present with significant pectus excavatum deformity.

Drug-Eluting Introducer Sheath Prevents Local Peripheral Complications : Pre-Clinical Evaluation of Nitric Oxide–Coated Sheath

OBJECTIVESnThis study evaluated the protective effect of nitric oxide-coating of introducer sheath on the local complications in juvenile porcine femoral arteries with similar size to human radial arteries.nnnBACKGROUNDnInsertion of an introducer sheath induces vasospasm and transient or permanent vessel occlusion of radial arteries.nnnMETHODSnNitric oxide-coated or control introducer sheaths with or without spasmolytic cocktail (control + C-sheath) were inserted into porcine femoral arteries, followed by percutaneous coronary intervention (PCI). The diameter of the femoral artery at the puncture site, distally and proximally, was measured by quantitative angiography. Histopathological and histomorphometric parameters of the femoral arteries were analyzed 1 h or 1 week after PCI.nnnRESULTSnInsertion of femoral sheath led to mild or severe spasms, with significantly higher vessel diameter at the access site (2.69 ± 0.81 mm vs. 1.77 ± 0.77 mm and 1.85 ± 0.66 mm, p < 0.001), and proximal and distal to it, during PCI in the nitric oxide-sheath group versus the control-sheath and control + C-sheath groups, respectively. Immediately following PCI, significantly less luminal thrombosis (12% vs. 33% and 31% of all analyzed segments, p < 0.001) was observed in the nitric oxide-sheath arteries. At 1 week, lower intimal inflammation score (0.43 ± 11 vs. 1.03 ± 0.35 and 1.04 ± 0.32, p < 0.05), less luminal thrombosis (8% vs. 21% and 30% p < 0.05), and smaller intimal hyperplasia (0.31 ± 0.31 mm(2) vs. 0.47 ± 1.00 mm(2) and 0.86 ± 0.82 mm(2), p < 0.05) were observed in NO-sheath arteries at the injury site.nnnCONCLUSIONSnNitric oxide coating on the introducer sheath prevents local complications during PCI and results in less vascular thrombosis and inflammation at the access site, contributing to patency of the access vessel with similar size to the radial artery.

Long-term outcome after thrombectomy in acute myocardial infarction.

Eur J Clin Invest 2010; 40 (3): 233–241

Prognostic value of culprit site neutrophils in acute coronary syndrome.

Recent data suggest that acute coronary syndromes (ACS) and acute myocardial infarction (AMI) are characterized by an inflammatory subset of thrombosis. We have previously described the accumulation of neutrophils at the coronary culprit lesion site. In this work, we assessed the prognostic value of culprit site (CS) neutrophil accumulation on long‐term mortality in patients with AMI.