[Follow-up after surgical treatment of type A acute aortic dissection: current evidence and controversies]. / Follow-up dei pazienti sottoposti ad intervento per dissezione aortica acuta di tipo A: evidenze e controversie.

Type A acute aortic dissection (TA-AAD) is a catastrophic condition for which emergency surgery is the mainstay of therapy. Surgical treatment of TA-AAD is centered on excision of the proximal intimal tear, replacement of the ascending aorta and re-establishment of a dominant flow in the distal true lumen. In patients who survive surgery, a dissected distal and/or proximal aorta remains, posing a risk of subsequent aneurysmal degeneration, rupture and malperfusion, and secondary extensive interventions are often required. However, knowledge regarding the risk factors of progression of residual aortic dissection is limited, and no well-defined recommendations for clinical and imaging follow-up have been generated thus far. The aim of this paper is to review and discuss on the current evidence and controversies on the long-term management of patients operated on for TA-AAD.

Expression of Nik-related kinase in smooth muscle cells attenuates vascular inflammation and intimal hyperplasia.

Inflammation of the vascular microenvironment modulates distinct types of vascular cells, and plays important roles in promoting atherosclerosis, stenosis/restenosis, and vascular-related diseases. Nik-related kinase (Nrk), a member of the Ste20-type kinase family, has been reported to be selectively expressed in embryonic skeletal muscle. However, whether Nrk is expressed in adult vascular smooth muscle, and if it influences intimal hyperplasia is unclear. Here, we found that Nrk is abundantly expressed in cultured vascular smooth muscle cells (VSMC) and mouse arterial intima. Treatment of mouse VSMCs with lipopolysaccharide (LPS) or platelet-derived growth factor significantly reduced Nrk expression. In addition, expression of Nrk was significantly reduced in regions of neointimal formation caused by guide-wire carotid artery injuries in mice, as well as in human atherosclerotic tissues, when compared to normal vessels. We identified that expression of matrix metalloproteinases (MMP3, MMP8 and MMP12) and inflammatory cytokines/chemokines (CCL6, CCL8, CCL11, CXCL1, CXCL3, CXCL5 and CXCL9) are synergistically induced by Nrk siRNA in LPS-treated mouse VSMCs. Moreover, we found that resveratrol significantly impaired LPS- and Nrk siRNA-induced expression of MMP3, CCL8, CCL11, CXCL3 and CXCL5. These results suggested that Nrk may play important roles in regulating pathological progression of atherosclerosis or neointimal- hyperplasia-related vascular diseases.

Platelet-derived microvesicles promote endothelial progenitor cell proliferation in intimal injury by delivering TGF-ß1.

Intimal injury is an early stage of several cardiovascular diseases. Endothelial progenitor cells (EPCs) play a significant role in endothelial repair following vascular injury. Once the intima is damaged, EPCs are mobilized from the bone marrow to the injury site. Meanwhile, the injury to the intimal surface triggers platelet degranulation, aggregation, and adhesion to the damaged endothelium, and exposed collagen stimulates platelet to secrete platelet-derived microvesicles (PMVs). However, the role of PMVs in EPC function during this process remains unknown. In an in vivo study, EPCs and platelets were found to adhere to the injury site in Sprague-Dawley (SD) rat vascular injury model. In vitro, collagen stimulation induced the release of PMVs, and collagen-activated PMVs (ac.PMVs) significantly promoted EPC proliferation. Transforming growth factor-ß1 (TGF-ß1) content was increased in ac.PMVs. Activated PMVs significantly upregulated Smad3 phosphorylation in EPCs and increased Smad3 nuclear translocation from the cytoplasm. TGF-ß1 knockdown ac.PMVs downregulated EPC proliferation. Recombinant TGF-ß1 enhanced EPC proliferation. The TGF-ß1 inhibitor SB431542 significantly repressed the intracellular signal triggered by ac.PMVs. Furthermore, the Smad3-specific phosphorylation inhibitor SIS3 effectively reversed the cell proliferation induced by ac.PMVs. Smad3 translocated to the nucleus and enhanced EPC proliferation via its downstream genes tenascin C (TNC), CDKN1A, and CDKN2A. r-TGF-ß1 promoted reendothelialization and EPC proliferation in vivo. Our data demonstrate that activated PMVs deliver TGF-ß1 from collagen-activated platelets to EPCs, which in turn activates Smad3 phosphorylation and regulates TNC, CDKN1A, and CDKN2A expression to promote EPC proliferation, suggesting that PMVs act as a key transporter and a potential therapeutic target for vascular injury.

Impact of Supraaortic Intimal Tears on Aortic Diameter Changes After Nontotal Arch Replacement.

BACKGROUND: This study evaluated the impact of the intimal tear location on aortic dilation and reintervention after nontotal arch replacement (non-TAR) for acute type I aortic dissection. METHODS: Between 2009 and 2017, 92 patients who underwent non-TAR for acute type I aortic dissection were enrolled. Intimal tears were analyzed at the supraaortic (SA) segment; segment 1, proximal descending thoracic aorta (DTA); segment 2, distal DTA; and segment 3, abdominal aorta. Aortic diameter was measured at the pulmonary artery bifurcation, celiac axis, maximal abdominal aorta, and maximal thoracoabdominal aorta using serial follow-up computed tomographic scans. The Fisher exact or χ2 test, independent t or Mann-Whitney U test, and log-rank test were used in the statistical analyses. RESULTS: The significant factors for increasing aortic diameter were the first location of intimal tear in the SA segment and segments 1 and 2. In the adjusted analysis, the first location of intimal tear in the SA segment and segment 1 was statistically significant. In the additional adjusted analysis, a segment 1 tear without SA tear was the only significant factor for increasing aortic diameter. The 5-year freedom from reintervention rate was significantly higher in patients with no intimal tear than in those with a segment 1 intimal tear with/without SA tear. CONCLUSIONS: We confirmed that SA and proximal DTA intimal tears are associated with subsequent aortic dilation and reintervention. These proximal aortic intimal tears might warrant aggressive surgical treatment at the initial operation or close postoperative follow-up.

Beta-blockers in non-surgical patients with type A aortic dissection.

Type A aortic dissection (TAAD) is a catastrophic condition with 24-48% mortality during the first day, if patients are not surgically treated. Due to old age and associated co-morbidities surgeons may be reluctant to operate and patients are administered medical therapy for the end of reducing systolic blood pressure and heart rate. Beta-blockers (BB) are the "medications of choice". Based on physical and physiological considerations, it was hypothesized that BB may actually exacerbate TAAD.

Treating Intimal Injury to the Graft Hepatic Artery by Intraoperative Fluorescence Vascular Stenting.

BACKGROUND: Early hepatic artery (HA) thrombosis and primary graft failure contribute greatly to the mortality of patients after liver transplantation. Herein, we present the treatment of intimal injury of HA by intraoperative fluorescence vascular stenting. METHODS: A sample of 471 patients receiving liver transplantations underwent arterial anastomosis. Six patients (1.3%) were found to have early HA thrombosis. Two patients had thrombi that were impenetrable with a guide wire. Intimal injury on both the graft and the donor sides of the HA was found after thrombectomy. We performed anastomosis between unhealthy graft vessels and healthy recipient vessels. Intraoperative angiography was done immediately because of the guide wire being easier to insert through a fresh thrombus, and a long endovascular stent was inserted to bypass the injured vessels. RESULTS: The proper HA was reconstructed under microscopy. Three days after reconstruction, an angioplasty showed no dissection, stenosis, or pseudoaneurysm of the HA. Unexpectedly, these 2 patients survived well with acceptable graft functionality, one based on a 32-month follow-up and the other based on a 2-month follow-up. CONCLUSION: Anastomosis of the intimally injured graft artery followed by immediate endovascular angioplasty with stenting to bypass the injury zone is an efficacious and tolerable procedure.

Dihydroartemisinin ameliorates balloon injury-induced neointimal formation in rats.

OBJECTIVES: This study aims to evaluate the effects of dihydroartemisinin (DHA) on the balloon injury-induced neointimal formation in rats and to investigate the underlying mechanism. METHODS: The balloon-induced carotid artery injury model was established in male Sprague-Dawley rats, immediately after which the DHA solution was injected into the tail vein of rats. In in vitro assays, primary rat vascular smooth muscle cells (VSMCs) were pretreated with DHA and then coincubated with LPS. RESULTS: DHA ameliorated the induced neointimal formation and fibrosis but enhanced apoptosis in rat carotid artery after balloon injury. Furthermore, DHA suppressed migration and enhanced apoptosis of the lipopolysaccharide (LPS)-treated primary VSMCs in vitro. Moreover, in both the balloon injury-induced rat sera and the LPS-treated VSMCs, DHA significantly inhibited proinflammatory cytokines, including interleukin-1ß, tumor necrosis factor-ɑ, and matrix metalloproteinase-1. Importantly, DHA significantly decreased the balloon injury-increased expression of nuclear factor kappa B (NF-κB) subunit NF-κB p65 expression, and increased the balloon injury-reduced expression of inhibitor of NF-κB-alpha, indicating the inhibition of the IκB/NF-κB pathway. CONCLUSION: DHA significantly inhibited neointimal formation in balloon-induced rat carotid artery injury and the mechanism may be related to the inhibition of IκB/NF-κB signaling, which alleviates the inflammatory response.

Noninvasive in vivo Assessment of the Re-endothelialization Process Using Ultrasound Biomicroscopy in the Rat Carotid Artery Balloon Injury Model.

OBJECTIVES: Ultrasound biomicroscopy (UBM), or ultra high-frequency ultrasound, is a technique used to assess the anatomy of small research animals. In this study, UBM was used to assess differences in intimal hyperplasia thickness as a surrogate measurement of the re-endothelialization process after carotid artery balloon injury in rats. METHODS: Ultrasound biomicroscopic data from 3 different experiments and rat strains (Sprague Dawley, Wistar, and diabetic Goto-Kakizaki) were analyzed. All animals were subjected to carotid artery balloon injury and examined with UBM (30-70 MHz) 2 and 4 weeks after injury. Re-endothelialization on UBM was defined as the length from the carotid bifurcation to the most distal visible edge of the intimal hyperplasia. En face staining with Evans blue dye was performed at euthanasia 4 weeks after injury, followed by tissue harvesting for histochemical and immunohistochemical evaluations. RESULTS: A significant correlation (Spearman r = 0.63; P < .0001) was identified when comparing all measurements of re-endothelialization obtained from UBM and en face staining. The findings revealed a similar pattern for all rat strains: Sprague Dawley (Spearman r = 0.70; P < .0001), Wistar (Spearman r = 0.36; P < .081), and Goto-Kakizaki (Spearman r = 0.70; P < .05). A Bland-Altman test showed agreement between en face staining and UBM. Immunohistochemical staining confirmed the presence of the endothelium in the areas detected as re-endothelialized by the UBM assessment. CONCLUSIONS: Ultrasound biomicroscopy can be used for repeated in vivo assessment of re-endothelialization after carotid artery balloon injury in rats.

Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis.

AIMS: Inflammatory mediators, including blood cells and their products, contribute critically to atherogenesis, but the igniting triggers of inflammation remain elusive. Atherosclerosis develops at sites of flow perturbation, where the enhanced haemodynamic stress could initiate the atherogenic inflammatory process due to the occurrence of mechanic injury. We investigated the role of haemodynamic stress-induced breaches, allowing the entry of blood cells in the arterial intima, in triggering inflammation-driven atherogenesis. METHODS AND RESULTS: Human coronary samples isolated from explanted hearts, (n = 47) displayed signs of blood entry (detected by the presence of iron, ferritin, and glycophorin A) in the subintimal space (54%) as assessed by histology, immunofluorescence, high resolution episcopic microscopy, and scanning electron microscopy. Computational flow dynamic analysis showed that intimal haemorrhagic events occurred at sites of flow disturbance. Experimental carotid arteries from Apoe deficient mice showed discrete endothelial breaches and intimal haemorrhagic events specifically occurring at the site of flow perturbation, within 3 days after the exacerbation of the local haemodynamic stress. Endothelial tearing was associated with increased VCAM-1 expression and, within 7 days, substantial Ly6G+ leucocytes accumulated at the sites of erythrocyte-derived iron and lipids droplets accumulation, pathological intimal thickening and positive oil red O staining. The formation of fatty streaks at the sites of intimal breaches was prevented by the depletion of Ly6G+ leucocytes, suggesting that the local injury driven by haemodynamic stress-induced breaches triggers atherogenic inflammation. CONCLUSION: Haemodynamic-driven breaches of the arterial intima drive atherogenic inflammation by triggering the recruitment of leucocyte at sites of disturbed arterial flow.

Iatrogenic Removal of the Intima in the Middle Cerebral Artery by a Stent Retriever: A Report of Two Cases.

BACKGROUND: Mechanical thrombectomy improves functional outcomes in patients with acute ischemic stroke. However, stent retrievers have the risk of vascular damage. CASE DESCRIPTION: We present 2 cases of patients with acute internal carotid artery occlusion who experienced removal of the intima by a stent retriever. In both patients, a 6 × 30-mm Solitaire stent was fully deployed from the M2 portion and slowly withdrawn. White membranes were retrieved outside the strut in both patients. Histopathologic examination showed that one membrane consisted of thickened intima and internal elastic lamina and the other consisted of calcified intima and internal elastic lamina. One patient who suffered embolic stroke experienced recurrent infarction within 24 hours after operation, and the damaged vessel was occluded on magnetic resonance angiography 21 days after stroke. In another patient with carotid artery dissection, the damaged vessel showed asymptomatic stenosis on magnetic resonance angiography 90 days after stroke. Arteries with both atherosclerosis and vessel dissection may be vulnerable to high radial expansion force. CONCLUSIONS: Full deployment of a relatively large-sized stent into a vulnerable vessel may cause vessel dissection after removal of the intima. Appropriate material selection and treatment strategy while considering stroke etiology and the occlusion site are important to prevent vessel damage.

Genetic lineage tracing analysis of c-kit+ stem/progenitor cells revealed a contribution to vascular injury-induced neointimal lesions.

AIMS: Accumulating evidence indicates the presence of vascular stem/progenitor cells that may play a role in endothelial repair and lesion formation in the injured artery, in which c-kit+ stem/progenitor cells have been reported to differentiate into endothelial and smooth muscle cells in vitro and in ischemic tissue. In this study, we investigated whether and how endogenous c-kit+ stem/progenitor cells contribute to vascular injury and neointima formation in vivo. METHODS AND RESULTS: We created Kit-CreERxRosa26-RFP mice and performed genetic lineage tracing analysis of c-kit+ stem/progenitor cells in injury-induced neointima formation in vivo. We provide direct evidence that endogenous c-kit+ stem/progenitor cells minimally differentiate into endothelial or smooth muscle cells facilitating vascular repair, but predominantly generate monocytes/macrophages and granulocytes contributing to vascular immuno-inflammatory response to endothelial injury. Although c-kit+ cells reside in both bone marrow and vessel wall, bone marrow transplantation data indicate that bone marrow-derived c-kit+ cells are the main source for enhancing neointima formation. Furthermore, treatment of ACK2, a c-kit receptor antagonizer, attenuates neointimal hyperplasia after injury at least in part by depleting c-kit+ cells and their generated progeny. CONCLUSIONS: c-kit+ stem/progenitor cells are not a main source for endothelial regeneration and smooth muscle accumulation of the large artery injury, but a plausible interventional approach to reduce vascular immuno-inflammatory response and subsequently to ameliorate vascular lesions.

Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion.

RATIONALE: Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant. OBJECTIVE: This study tested the hypothesis that PAD4 and NETs influence experimental atherogenesis and in processes implicated in superficial erosion, a form of plaque complication we previously associated with NETs. METHODS AND RESULTS: Bone marrow chimeric Ldlr deficient mice reconstituted with either wild-type or PAD4-deficient cells underwent studies that assessed atheroma formation or procedures designed to probe mechanisms related to superficial erosion. PAD4 deficiency neither retarded fatty streak formation nor reduced plaque size or inflammation in bone marrow chimeric mice that consumed an atherogenic diet. In contrast, either a PAD4 deficiency in bone marrow-derived cells or administration of DNaseI to disrupt NETs decreased the extent of arterial intimal injury in mice with arterial lesions tailored to recapitulate characteristics of human atheroma complicated by erosion. CONCLUSIONS: These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.

Ascending Aortic Rupture through a Penetrating Atherosclerotic Ulcer: A Rare Cause of Sudden Unexpected Death.

Spontaneous rupture of the aorta through an atherosclerotic lesion without preexisting aortic aneurysm, dissection, or history of trauma is very rare. Without prompt aortic repair, all cases result in sudden death with a definitive diagnosis made only intraoperatively or during autopsy. The phenomenon has been uniformly found in individuals with hypertension. The author reports a sudden unexpected death caused by spontaneous rupture of the ascending aorta in a 57-year-old man with a history of hypertension. The ascending aortic wall showed a longitudinal intimal tear measuring approximately 1 cm in length and rupture of the ascending aorta through an atherosclerotic ulcer, leading to massive hemopericardium and eventual death. Chronic hypertension and a penetrating atherosclerotic ulcer of the ascending aorta were the apparent underlying etiologies of the aortic rupture in the present case. This case illustrates not only the association between a rupture and a penetrating atherosclerotic ulcer with a silent death, but also raises awareness of possible such deaths.

Locally Transplanted CD34+ Bone Marrow-Derived Cells Contribute to Vascular Healing After Vascular Injury.

INTRODUCTION: Vascular progenitor cells contribute to repair of injured vasculature. In this study, we aimed to investigate the role of bone marrow-derived cells in the intimal formation after arterial injury. METHODS AND RESULTS: Balloon injury of the femoral artery of wild-type mice was followed by local delivery of bone marrow-derived cells from GFP transgenic mice. The arteries were collected 1, 4, 7, and 14 days after injury and studied for morphology, localization, and phenotypes of delivered cells. Bone marrow-derived cells were present in the intima only at the early stages of arterial injury and expressed endothelial progenitor cell markers (CD31, CD34, and VEGFR-2). In the areas where intima was thicker, bone marrow-derived cells differentiated to intimal smooth muscle cells but they did not fuse with intimal cells. Delivery of CD34+ cells contributed to a 1.5-fold inhibition of intimal hyperplasia. CONCLUSION: Bone marrow-derived endothelial cells differentiated but did not fuse with vascular smooth muscle cells at the early stages of intimal formation and contributed to intimal hyperplasia.

Resident Arterial Cells and Circulating Bone Marrow-Derived Cells both Contribute to Intimal Hyperplasia in a Rat Allograft Carotid Transplantation Model.

BACKGROUND/AIMS: Neointimal formation following vascular injury remains a major mechanism of restenosis, whereas the precise sources of neointimal cells are still uncertain. We tested the hypothesis that both injured arterial cells and non-arterial cells contribute to intimal hyperplasia. METHODS: Following allograft transplantation of the balloon-injured carotid common artery (n = 3-6), the cellular composition of the transplant grafts and the origins of neointimal cells were measured by immunohistochemistry and immunofluorescence staining. RESULTS: Smooth muscle actin (SMA)-positive and CD68-positive cells were clearly observed 14 days later in the neointima after allograft transplantation of the balloon-injured carotid common artery, where re-endothelialization was not yet complete. Green fluorescent protein (GFP) and wild-type (WT) allograft transplantation revealed that the majority of the neointima cells were apparently from the recipient (≈85%) versus the donor (≈15%). Both monocyte chemotactic protein-1 (MCP-1)/CCR2 and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling were involved in intimal hyperplasia, with bone marrow-derived cells also playing a role. CONCLUSION: These data support the hypothesis that intimal hyperplasia could develop in our novel rat allograft transplantation model of arterial injury, where neointima is attributable not only to local arterial cells but also non-arterial cells including the bone marrow.

Intima migration from the iliac artery to a debranched graft after thoracic endovascular aortic repair.

An 84-year-old woman underwent single-debranched thoracic endovascular aortic repair for aortic aneurysm. A few hours later, malperfusion of the left upper extremity occurred. Surgical exploration revealed a tubular-shaped intima packed in the debranched graft. As computed tomography showed localized dissection in the right external iliac artery probably due to access route injury, the intima roll was thought to have migrated from the iliac artery. This extremely rare case is described in detail with a discussion of the potential mechanism.

A pitfall of false lumen embolization in chronic aortic dissection: intimal injury caused by the embolization device edge.

We report a case of intimal injury caused by the occluder device in the false lumen (FL) after treatment of refractory chronic aortic dissection with FL embolization. We speculate that the intimal injury was due to the disproportionate stress from the FL. We covered the new entry by an additional stent graft in the true lumen. The deployment of a stent device in both lumens at the level of embolization might be indispensable for FL embolization.

Pseudo-tying injuries in a hanged person.

A 50-year-old man was found hanged on the concrete dam of a water reservoir. The ligature, a braided rope made of synthetic fibres, was attached to a lamp on the dam crest. The length of the rope between the fastening point and the noose was about 4m. At autopsy, stretchmark-like intimal tears of the carotid arteries were found, but the full pattern of (internal) decapitation and severance of the cervical spine was not present. The right wrist showed two almost circular, ribbon-like abrasions initially suggesting that the man had been tied before hanging. When the ligature was examined, horny scales adhered to the noose, but were also detected away from the slip-knot. By means of a DNA analysis the epidermal traces could be assigned to the deceased. The overall picture of the findings suggested that the man had roped down from the dam crest with the ligature wrapped around his right wrist thus abrading the skin.