Outcome of valve sparing root replacement for diverse indications.

OBJECTIVES: We report the mid-term outcomes of valve-sparing aortic root replacement (VSRR) in a cohort including patients with bicuspid aortic valve (BAV), connective tissue disorder (CTD), aortic dissection (AD), and congenital heart disease (CHD). Design. From 2005 to 2017, 174 patients underwent VSRR with the reimplantation technique. The mean age was 46 ± 14 years. The mean follow-up time was 4.8 ± 2.8 years. The indication for operation was aortic aneurysm for 127 (73%), aortic insufficiency (AI) for 38 (22%), and AD for 9 patients (5%). Preoperatively, 53 patients (31%) had ≥ moderate AI. BAV, CTD (Marfan or Loyes-Dietz), previous Ross procedure, or CHD was present in 57 (33%), 28 (16%), 7 (4%) and 12 patients (7%), respectively. Concomitant aortic valve repair was performed for 103 patients (59%). Results. Thirty-day mortality was zero. Four patients underwent aortic valve replacement (AVR) during follow-up. Kaplan-Meier estimates for survival, freedom from AVR, and freedom from ≥ moderate AI or reoperation were 96, 98, and 97% at 5 years. There was no difference in survival, freedom from AVR, or freedom from ≥ moderate AI or reoperation in patients with and without BAV, CTD, leaflet repair, or preoperative ≥ moderate AI. In Cox regression analysis, BAV, CTD, aortic valve repair, preoperative ≥ moderate AI, or aortic dimension were not risk factors for reoperation or valve dysfunction. Conclusions. Mid-term outcomes of VSRR for patients with diverse indications in terms of survival, reoperation rate, and valve dysfunction rate were excellent in a center with a limited annual volume of VSSR.

Epitranscriptomics of Ischemic Heart Disease-The IHD-EPITRAN Study Design and Objectives.

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.

Critical role of VEGF-C/VEGFR-3 signaling in innate and adaptive immune responses in experimental obliterative bronchiolitis.

Chronic inflammation, a hallmark of obliterative bronchiolitis, is known to induce lymphangiogenesis. We therefore studied the role of lymphangiogenic vascular endothelial growth factor C (VEGF-C), its receptor VEGFR-3, and lymphangiogenesis during development of experimental obliterative bronchiolitis [ie, obliterative airway disease (OAD)] in rat tracheal allografts. The functional importance of VEGF-C was investigated by adenovirus-mediated overexpression of VEGF-C (AdVEGF-C), and by inhibition of VEGF-C activity with VEGFR-3-Ig (AdVEGFR-3-Ig). Analyses included histology, immunohistochemistry, and real-time RT-PCR 10 and 30 days after transplantation. In the course of OAD development, lymphangiogenesis was induced in the airway wall during the alloimmune response, which was reversed by cyclosporine A in a dose-dependent fashion. VEGF-C overexpression in tracheal allografts induced epithelial activation, neutrophil chemotaxis, and a shift toward a Th17 adaptive immune response, followed by enhanced lymphangiogenesis and the development of OAD. In contrast, inhibition of VEGF-C activity with VEGFR-3-Ig inhibited lymphangiogenesis and angiogenesis and reduced infiltration of CD4(+) T cells and the development of OAD. Lymphangiogenesis was linked to T-cell responses during the development of OAD, and VEGF-C/VEGFR-3 signaling modulated innate and adaptive immune responses in the development of OAD in rat tracheal allografts. Our results thus suggest VEGFR-3-signaling as a novel strategy to regulate T-cell responses in the development of obliterative bronchiolitis after lung transplantation.

Upregulation of Coagulation Factor VIII and Fibrinogen After Pulmonary Endarterectomy in Patients with Chronic Thromboembolic Pulmonary Hypertension.

OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with thrombotic states including elevated coagulation factor VIII (FVIII). Pulmonary endarterectomy (PEA) is the main treatment for CTEPH, and efficient anticoagulation is essential to prevent thromboembolism recurrence after surgery. We aimed to characterize longitudinal changes in FVIII and other coagulation biomarkers after PEA. METHODS: Coagulation biomarker levels were measured at baseline and up to 12 months after operation in 17 consecutive patients with PEA. Temporal patterns of coagulation biomarkers, and correlation of FVIII with other coagulation biomarkers, were analyzed. RESULTS: Baseline FVIII levels were elevated in 71% of the patients (mean 216 ± 67 IU/dl). FVIII doubled 7 days after PEA, peaking at 471 ± 87 IU/dl, and gradually returned to respective baseline levels within 3 months. Postoperative fibrinogen levels were also elevated. Antithrombin decreased at 1 to 3 days, D-dimer increased at 1 to 4 weeks, and thrombocytosis was observed at 2 weeks. CONCLUSIONS: FVIII is elevated in most patients with CTEPH. After PEA, early but transient elevation of FVIII and fibrinogen, and delayed reactive thrombocytosis, occurs, and warrants careful postoperative anticoagulation to prevent thromboembolism recurrence.

[Diagnosis and treatment of chylothorax]. / Kylothoraxin diagnoosi ja hoito.

In chylothorax, chyle has accumulated into the pleural clarity. Chylothorax is a fairly rare finding, most commonly arising after procedures within the thoracic cavity. Suspicion of chylothorax is based on anamnesis and clinical picture, with chest radiograph and pleural fluid puncture as the basic tests. Treatment should be started immediately after a confirmed diagnosis. In the early stages it is vital that the production of chyle is minimized and the fluid is drained. If the conservative treatment fails, surgery is recommended

Valve-sparing aortic root replacement in adult patients previously operated for congenital heart defects: an initial experience.

OBJECTIVES: To review our experience with valve-sparing aortic root replacement (VSARR) in adult patients after the previous surgery for congenital heart disease. METHODS: From August 2008 to February 2014, 11 patients (mean age: 30.5 ± 7.7 years), previously operated for various congenital cardiac defects, mostly conotruncal lesions, underwent VSARR for progressive aortic root dilatation. Five patients had also developed moderate, and 1 patient severe aortic valve (AoV) insufficiency. All aortic root procedures were performed by the same operating surgeon in two institutions. The mean interval between the initial procedure and aortic root surgery was 25.7 ± 7.7 years. At the time of reoperation, the mean aortic root diameter was 53.4 ± 6.2 mm. The reimplantation technique (David procedure) was used in all patients. Seven patients underwent concomitant procedures. The median follow-up was 32 months (range 12-78 months). RESULTS: No mortality occurred in hospital or during the follow-up period. Ten patients remain in NYHA functional class I; 1 patient with a single-ventricle circulation is in NYHA functional class II. During the immediate postoperative period, 2 patients underwent drainage of a pericardial collection and 1 patient required renal replacement therapy with eventual full recovery of renal function. No other reoperations or reinterventions were needed during the follow-up period. The most recent echocardiogram in 10 patients have demonstrated no or trivial AoV insufficiency. One patient, however, with severe aortic insufficiency preoperatively, developed mild AoV regurgitation shortly after the operation, which has progressed to moderate regurgitation 1 year following the operation. CONCLUSIONS: Analysis of our experience in a small group of patients confirms that valve-sparing aortic root surgery can be safely performed in adult congenital patients presenting with progressive aortic root dilatation following their previous surgery. Although we have analysed patients with different original congenital cardiac lesions and the follow-up period is not long, we can conclude that the use of the reimplantation technique (David procedure) have resulted in overall satisfactory AoV function at follow-up. Longer follow-up with larger series will be needed, however, before firm conclusions can be drawn.

Increased myeloid cell hypoxia-inducible factor-1 delays obliterative airway disease in the mouse.

BACKGROUND: Obliterative bronchiolitis after lung transplantation is characterized by chronic airway inflammation leading to the obliteration of small airways. Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular responses to hypoxia and inflammation. The Von Hippel-Lindau protein (pVHL) drives the degradation of oxygen-sensitive subunit HIF-1α that controls the activity of HIF-1. We investigated the effect of myeloid cell-targeted gene deletion of HIF-1α or its negative regulator pVHL on the development of obliterative airway disease (OAD) in the recipients of tracheal allografts, a mouse model for obliterative bronchiolitis after lung transplantation. METHODS: Tracheal allografts were heterotopically transplanted from BALB/c donor mice to fully major histocompatibility complex-mismatched recipient mice with HIF-1α or VHL gene deletion in myeloid cells. The recipients were left non-immunosuppressed or received tacrolimus daily. Histologic, immunohistochemical, and real-time reverse transcription polymerase chain reaction analyses were performed at 3, 10, and 30 days. RESULTS: In the absence of immunosuppression, myeloid cell-specific VHL deficiency of the recipient mice improved epithelial recovery, decreased inflammatory cell infiltration and expression of pro-inflammatory cytokines, increased regulatory forkhead box P3 messenger RNA expression, and reduced OAD development in tracheal allografts. In the presence of tacrolimus immunosuppression, loss of HIF-1α activity in myeloid cells of the recipient by HIF-1α gene deletion accelerated OAD development in mouse tracheal allografts. CONCLUSIONS: Activity of the HIF-pathway affects the development of allograft rejection, and our results suggest that myeloid cell-specific VHL-deficiency that potentially increases HIF-activity decreases allograft inflammation and the subsequent development of OAD in mouse tracheal allografts.

Effect of simvastatin on development of obliterative airway disease: an experimental study.

BACKGROUND: Obliterative bronchiolitis after lung transplantation is characterized by airway inflammation leading to obliteration of small airways. Statins are known to have lipid-independent immunomodulatory properties. We investigated the effect of simvastatin treatment on innate and adaptive immune responses and the development of obliterative airway disease (OAD). METHODS: In fully MHC-mismatched rat tracheal allograft recipients, we used simvastatin at different doses (0.1 to 20 mg/kg/day orally) to assess its effect on OAD development. No immunosuppressive treatment was administered. Histologic, immunohistochemical and real-time RT-PCR analyses were performed 3, 10 and 30 days after transplantation. RESULTS: Simvastatin treatment with doses ranging from 0.5 to 20 mg/kg/day significantly enhanced early epithelial recovery and reduced the development of OAD. No dose response was observed. Simvastatin treatment markedly reduced IL-23 mRNA and lymphocyte chemokine CCL20 production, and the infiltration of CD4(+) and CD8(+) T cells into allografts already at 3 days. At 10 days, simvastatin significantly attenuated the production of pro-inflammatory cytokines, IL-1ß, TNF-α, MCP-1 and IP-10, and Th17-polarizing cytokines, IL-6 and IL-17e, and inhibited allograft infiltration by inflammatory cells. The protective effects of simvastatin on inflammation and OAD were partially mediated through nitric oxide synthase. CONCLUSIONS: Simvastatin treatment inhibited adaptive T-cell alloimmune activation as depicted by reduced expression of lymphocyte chemokine and pro-inflammatory cytokine mRNA and reduced allograft infiltration by inflammatory cells. Importantly, simvastatin inhibits the development of OAD and this effect is partially mediated by increased nitric oxide activity. These results suggest a role for simvastatin in the prevention of obliterative bronchiolitis.

Innate and adaptive immune responses in obliterative airway disease in rat tracheal allografts.

BACKGROUND: We assessed cellular innate and adaptive immune responses in a rat heterotopic tracheal allograft model during the development of obliterative airway disease. METHODS: Syngeneic tracheal grafts were transplanted heterotopically from DA to DA rats and fully MHC-mismatched allografts from DA to WF rats. The recipients received either no immunosuppression or two different doses of cyclosporine and were euthanized at 3, 10 and 30 days. Non-transplanted DA tracheas served as controls. Histologic, immunohistochemical and real-time RT-PCR analyses were performed. RESULTS: The syngrafts had normal epithelium at 10 days and no tracheal occlusion was seen at 30 days. In non-immunosuppressed allografts, almost total loss of epithelium was observed at 10 days, culminating in tracheal occlusion at 30 days. The activation of innate immune response was observed during the ischemic period at 3 days in both groups. Influx of the infiltrating inflammatory cells was more prominent in the allografts. In syngrafts, mRNA expression of pro-inflammatory, but also tolerogenic, cytokines was significantly upregulated, whereas Th1 and Th17 priming factors were significantly downregulated. In allografts, prominent mRNA expression of pro-inflammatory cytokines was seen and adaptive Th1 and Th17 alloresponses were increased. Cyclosporine treatment reduced tracheal occlusion and inhibited both tolerogenic and pro-inflammatory T-cell responses in allografts. CONCLUSIONS: Ischemia induced a self-limiting, alloantigen-independent innate immune response in syngrafts. In allografts, the predominant pro-inflammatory milieu and alloantigen-dependent Th1 and Th17 responses were linked to the development of obliterative airway disease and were inhibited by cyclosporine treatment.