A. Dashkevich

Supracoronary ascending aortic replacement in patients with acute aortic dissection type A: What happens to the aortic root in the long run?

OBJECTIVE Our objective was to determine long-term outcome predictors for patients with acute aortic dissection type A (AADA) and aortic root involvement. METHODS From 2001 through 2009, 119 of 152 patients operated on for AADA at a tertiary medical center underwent supracoronary ascending aortic replacement (52 women; mean age, 61 ± 15 years). Those with at least 1-year follow-up (n = 97) were retrospectively assessed for preoperative aortic root disease. Follow-up data were assessed for evidence of new-onset aortic root disease by computed tomography and echocardiography, and for reoperation for aortic root disease. RESULTS Median follow-up was 33.8 months (range, 0-112 months). Twenty-six (27%) patients had new-onset aortic root disease at 4.4 ± 2.6 years after the initial procedure (range, 1.0-8.2 years) and 10 required aortic root reoperation. Severe aortic dissection with extension to pelvic arteries was an independent predictor for new-onset aortic root disease (P < .01). Dissection of all aortic sinuses during the initial procedure was an independent predictor (P < .05) for aortic root reoperation. Mean rate of aortic root expansion after supracoronary repair was 0.6 ± 1.1 mm per year. Preoperative aortic root diameter and aortic sinus dissection did not affect survivals. Five-year survivals were similar in patients with and without new-onset aortic root disease (91% vs 89%; P = .79). CONCLUSIONS In patients with AADA, dissection of 3 aortic sinuses is an independent predictor for need of reoperation, whereas dissection extension into the iliac arteries is a predictor of secondary aortic root disease. Long-term follow-up at close intervals is warranted in patients with supracoronary ascending aortic replacement to reduce mortality caused by new onset of aortic root disease.

Lymph Angiogenesis After Lung Transplantation and Relation to Acute Organ Rejection in Humans

BACKGROUND Acute rejection after kidney transplantation was found to be associated with increased recipient-derived lymph angiogenesis. However, the relation of lymph angiogenesis to acute rejection in lung transplantation has not yet been investigated. METHODS Transbronchial biopsies from 23 lung transplant recipients (47 + or - 15 years old, 15 male, 19 double lungs, 4 single lungs), taken at 14 and 90 days after transplantation were investigated. Immunohistostaining for PROX-1 (an lymphatic endothelial marker) and for vascular endothelial growth factor receptor (VEGFR) 1 and 2 (blood capillary markers) was performed. Biopsies with no sign of rejection (International Society for Heart and Lung Transplantation [ISHLT] grade A0, n = 27) were compared with biopsies with rejection grade A1/A2 (n = 19). RESULTS Biopsies with ISHLT rejection grade A1 or A2 showed a significantly higher density of PROX-1 marked lymphatics in comparison with biopsies of grade A0 at 14 days (p < 0.001) and at 90 days (p < 0.001) after transplantation, and in the collective comparison (all biopsies with ISHLT grade A1 or A2 versus all biopsies with grade A0, p < 0.001). For VEGFR-1 and VEGFR-2, no difference was found between ISHLT grade A1 or A2 compared with grade A0, neither at 14 or 90 days nor in the collective comparison. CONCLUSIONS Increased lymphatic angiogenesis after lung transplantation, demonstrated by increased density of the PROX-1 lymphatic endothelial marker, was associated with histologically evident acute organ rejection in humans. Although the exact role of lymphatic angiogenesis in acute organ rejection remains to be determined, further study of the interaction between the microvasculature and acute rejection seems warranted. Pending further investigation, analysis of PROX-1 density may develop into a new tool for rejection monitoring, supplementing conventional rejection grading.

VEGF Pathways in the Lymphatics of Healthy and Diseased Heart.

Cardiac lymphatic system is a rare focus of the modern cardiovascular research. Nevertheless, the growing body of evidence is depicting lymphatic endothelium as an important functional unit in healthy and diseased myocardium. Since the discovery of angiogenic VEGF‐A in 1983 and lymphangiogenic VEGF‐C in 1997, an increasing amount of knowledge has accumulated on the essential roles of VEGF ligands and receptors in physiological and pathological angiogenesis and lymphangiogenesis. Tissue adaptation to several stimuli such as hypoxia, pathogen invasion, degenerative process and inflammation often involves coordinated changes in both blood and lymphatic vessels. As lymphatic vessels are involved in the initiation and resolution of inflammation and regulation of tissue edema, VEGF family members may have important roles in myocardial lymphatics in healthy and in cardiac disease. We will review the properties of VEGF ligands and receptors concentrating on their lymphatic vessel effects first in normal myocardium and then in cardiac disease.

Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.

Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia–reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF‐C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF‐C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF‐C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF‐C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF‐C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF‐C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic‐targeted immunomodulatory therapy to prevent acute and chronic rejection.

Platelet-derived Growth Factor-B Protects Rat Cardiac Allografts From Ischemia-reperfusion Injury.

Background Microvascular dysfunction and cardiomyocyte injury are hallmarks of ischemia-reperfusion injury (IRI) after heart transplantation. Platelet-derived growth factors (PDGF) have an ambiguous role in this deleterious cascade. On one hand, PDGF may exert vascular stabilizing and antiapoptotic actions through endothelial-pericyte and endothelial-cardiomyocyte crosstalk in the heart; and on the other hand, PDGF signaling mediates neointimal formation and exacerbates chronic rejection in cardiac allografts. The balance between these potentially harmful and beneficial actions determines the final outcome of cardiac allografts. Methods and Results We transplanted cardiac allografts from Dark Agouti rat and Balb mouse donors to fully major histocompatibility complex-mismatched Wistar Furth rat or C57 mouse recipients with a clinically relevant 2-hour cold ischemia and 1-hour warm ischemia. Ex vivo intracoronary delivery of adenovirus-mediated gene transfer of recombinant human PDGF-BB upregulated messenger RNA expression of anti-mesenchymal transition and survival factors BMP-7 and Bcl-2 and preserved capillary density in rat cardiac allografts at day 10. In mouse cardiac allografts PDGF receptor-&bgr;, but not -&agr; intragraft messenger RNA levels were reduced and capillary protein localization was lost during IRI. The PDGF receptor tyrosine kinase inhibitor imatinib mesylate and a monoclonal antibody against PDGF receptor-&agr; enhanced myocardial damage evidenced by serum cardiac troponin T release in the rat and mouse cardiac allografts 6 hours after reperfusion, respectively. Moreover, imatinib mesylate enhanced rat cardiac allograft vasculopathy, cardiac fibrosis, and late allograft loss at day 56. Conclusions Our results suggest that PDGF-B signaling may play a role in endothelial and cardiomyocyte recovery from IRI after heart transplantation.

Training-related changes in muscular and myocardial lymphangiogenesis: how to train the drain?

Lymphatic vascular system is a relatively rare focus of the modern cardiovascular research. In this context, the paper published by Greiwe et al. (2015)in this journal seems to represent a very important body of new evidence concerning the influence of different training regimens on lymphangiogenesis and lymphatic vessel densities in skeletal muscles and myocardium. The lymphatic system has important roles in various essential body functions, such as fluid homoeostasis, intestinal lipid absorption and immune cell trafficking (Alitalo 2011). The very basic and utmost important function of the lymphatic system is doubtlessly the fluid homeostasis, which is highly relevant for the richly perfused muscle tissue. Thus, trainingrelated increase in tissue perfusion and secretion of metabolic waste would physiologically require increased capacity of the draining system. So, muscle training should normally be accompanied by drain training. However, this obvious hypothesis has never been addressed at the molecular or microscopic level. The authors provide novel insights into lymphangiogenesis and lymphatic vessel density regulation upon chronic training and show that both skeletal and cardiac muscles definitely, but controversially adapt to chronic training regimens: chronic eccentric muscle contraction reduced lymphatic vessel density in skeletal muscles but significantly elevated the density of myocardial lymphatics. To explain this controversy, the authors suggest three mechanisms. The first mechanism is that the lymphatics are destroyed due to direct exposure of the skeletal muscles to high mechanical stress, which is different in cardiac myocardium, where the protective components of lymphatic-specific extracellular matrix seem to provide a more stable environment. The second suggested mechanism is the negative impact of training-related inflammation, which was evidently increased in skeletal muscles, but not in myocardium. And the third mechanism was suggested to be an evident transformation of initial lymphatic capillaries into larger lymphatic vessels. The discussed mechanisms might reflect the different ways of physiological adaptation of muscular and myocardial lymphatics to chronic training. And the understanding of the underlying processes is important. In particular, the fact of training-related stimulation of cardiac lymphangiogenesis and increase in the density of myocardial lymphatics might have a potential clinical relevance. As reviewed recently (Dashkevich et al. 2016), very little is currently known about the role of lymphatics in various cardiac diseases. However, the training-related modulation of lymphatic endothelial phenotype and lymphatic density might have a hypothetical impact in several cardiac pathologies. For instance, in atherosclerotic lesions, the impaired lymphangiogenesis seems to contribute to sustained inflammatory reactions in human coronary atherogenesis (Nakano et al. 2005). Furthermore, lymphatics are pivotal in the process of healing after myocardial infarction, participating in fibrosis maturation and scar formation through the drainage of excessive proteins and fluid mediated by VEGF-C

Management of Retrograde False Lumen Perfusion After Hybrid Arch Repair in Acute Aortic Dissection

Patients with acute aortic dissections involving the arch and descending aorta can effectively be treated using the frozen elephant trunk technique. We describe here the novel technique of temporary banding of the descending aorta onto the stent of the hybrid graft in 3 patients who developed unmanageable bleeding from the distal suture line due to retrograde false lumen perfusion and disintegration of the adventitia. Retrograde false lumen perfusion was stopped and therefore bleeding controlled in all patients. Temporal aortic banding represents a novel, feasible, and effective bailout technique for otherwise unmanageable bleeding with fatal outcome in hybrid arch surgery.

Vascular Endothelial Growth Factor-B Overexpressing Hearts Are Not Protected From Transplant-Associated Ischemia-Reperfusion Injury.

OBJECTIVES Cardiac vascular endothelial growth factor-B transgene limits myocardial damage in rat infarction models. We investigated whether heart transplant vascular endothelial growth factor-B overexpression protected against ischemia-reperfusion injury. MATERIALS AND METHODS We transplanted hearts heterotopically from Dark Agouti to Wistar Furth rats. To characterize the role of vascular endothelial growth factor-B in ischemia-reperfusion injury, we transplanted either long-term human vascular endothelial growth factor-B transgene overexpressing hearts from Wistar Furth rats or short-term adeno-associated virus 9-human vascular endothelial growth factor-B-transduced hearts from Dark Agouti rats into Wistar Furth rats. Heart transplants were subjected to 2 hours of cold and 1 hour of warm ex vivo ischemia. Samples were collected 6 hours after reperfusion. RESULTS Two hours of cold and 1 hour of warm ischemia increased vascular endothelial growth factor-B mRNA levels 2-fold before transplant and 6 hours after reperfusion. Transgenic vascular endothelial growth factor-B overexpression caused mild cardiac hypertrophy and elevated cardiac troponin T levels 6 hours after reperfusion. Laser Doppler measurements indicated impaired epicardial tissue perfusion in these transgenic transplants. Recombinant human vascular endothelial growth factor-B increased mRNA levels of cytochrome c oxidase and extracellular ATPase CD39, suggesting active oxidative phosphorylation and high ATP production. Adeno-associated virus 9-mediated vascular endothelial growth factor-B overexpression in transplanted hearts increased intragraft macrophages 1.5-fold and proinflammatory cytokine interleukin 12 p35 mRNA 1.6-fold, without affecting recipient serum cardiac troponin T concentration. CONCLUSIONS Vascular endothelial growth factor-B expression in transplanted hearts is linked to ischemia and ischemia-reperfusion injury. Cardiac transgenic vascular endothelial growth factor-B overexpression failed to protect heart transplants from ischemia-reperfusion injury.

Should patients with challenging neck anatomy of non-dissected thoracic aortic disease be offered endovascular treatment?

Objectives: Suitable anatomy of landing zone (LZ) is essential for successful endovascular treatment of thoracic aortic aneurysm. Anatomic requirements include ≥20mm proximal and distal neck length, 20 to 42mm proximal and distal neck diameters and no extreme aortic tortuosity at LZ. We analysed outcome in patients with extremely difficult neck anatomy. Methods: In our centre, between 2000 and 2011, 208 endovascular treatments for descending thoracic aortic disease were performed. One-hundred-and-five patients with non-dissected thoracic aortic pathology were assessed for length, diameter and angulation of proximal and distal LZ. Challenging LZ was defined as presence of one or more of the following characteristics: very short length (45mm) and extreme aortic tortuosity at LZ (>90°). Perioperative mortality, 1- and 2-years-survival, endoleak type 1 occurrence and incidence of secondary intervention were compared between groups with challenging (n=52) and favorable (n=53) LZ anatomy. Results: Mean follow-up was 20 months (range, 1–156 months). Endovascular treatment was performed for emergent or urgent indications in 35% of patients with challenging LZ and in 28% of patients with favorable LZ (p=0.4). Perioperative mortality was equal for both groups (1.9%). Intra-operative rupture or need for open conversion were not observed in either group. Postoperative hemi- or paraparesis occurred in 6% of patients with challenging and 2% with favorable LZ (p=0.3). Frequency of endoleak type 1 was comparable in both groups with challenging and favorable LZ (15% vs. 19%, p=0.8). Secondary intervention rate was identical in both groups (15%). One and 2 year survival were similar in both challenging and favourable LZ groups (94% vs. 91%, p=0.7; 90% vs. 89%, p=1). Conclusions: Patients with challenging neck anatomy of non-dissected thoracic aortic disease should be offered endovascular treatment, since their initial mortality rate, incidence of endoleak type 1 and need for secondary intervention were similar to that in patients with favorable LZ. Intermediate technical results were acceptable despite extreme difficult LZ anatomy.