Objectives This study assessed the rate of periprocedural embolic ischemic brain injury during transapical aortic valve replacement in 25 consecutive patients. Background Transcatheter aortic valve ...implantation is rapidly being established as a new therapeutic approach for aortic valve stenosis. Although initial clinical results are promising, it is unknown whether mobilization and embolization of calcified particles may lead to cerebral ischemia. Methods Twenty-five consecutive patients (10 men, 15 women, mean age: 81 ± 5 years, mean log EuroSCORE European System for Cardiac Operative Risk Evaluation: 32 ± 10%) scheduled for transapical aortic valve implantation were included. All patients received a baseline cerebral magnetic resonance imaging scan. The scan was repeated approximately 6 days after valve implantation. The magnetic resonance imaging studies included axial diffusion–weighted, T2 -weighted, fluid attenuated inversion recovery–weighted, and T2 gradient echo sequences. Standardized assessment of the neurologic status was performed before aortic valve replacement and post-operatively. Results Transapical aortic valve implantation was successfully performed in all patients. In 17 patients (68%), new cerebral lesions could be detected, whereas 8 patients showed no new cerebral insults. The pattern of distribution and morphology were typical of embolic origin. Despite the high incidence of morphologically detectable lesions, only 5 patients showed clinical neurologic alterations. Out of these patients, only 1 suffered from a permanent stroke. Conclusions New embolic ischemic cerebral insults are detected in 68% of patients after transapical valve implantation. Clinical symptoms are rare and usually transitory. Larger trials will need to establish the clinical significance of asymptomatic ischemic lesions as well as the rate of ischemic events in patients undergoing transfemoral valve replacement.
Prior studies have shown that cytomegalovirus (CMV) infection is a risk factor for the development of cardiac allograft vasculopathy (CAV) and is associated with reduced long-term survival after ...heart transplantation (HTx). The aim of this International Society for Heart and Lung Transplantation Transplant Registry study was to compare posttransplant survival in different CMV donor:recipient serologic combinations.
We performed a retrospective cohort study, using the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, on 15 885 adult primary heart transplant recipients with known CMV serologic status between July 2004 and June 2014. Posttransplant survival and risk of developing CAV were compared across 4 groups: CMV-seronegative recipients (R-) receiving CMV-positive grafts (D+), intermediate-risk patients (D+R+ and D-R+), and low-risk patients (D-R-).
Baseline characteristics (donor/recipient age, body mass index, recipient serum creatinine, blood group, donor cause of death, recipient diagnosis, and ischemic time) were mostly balanced between the groups. Kaplan-Meier survival analyses over a follow-up of 10 y revealed significantly worse survival for both D+ groups as compared to the CMV low-risk group (D+R+: 56.61% 95% confidence interval, 53.94-59.41 versus D-R-: 63.09% 59.74-66.64 P < 0.01 and D+R-: 57.69% 56.03-59.39 versus D-R-; P < 0.001), whereas recipient seropositivity alone was not associated with reduced survival (D-R+ versus D-R-P = 0.178). The risk of developing CAV after HTx was not significantly increased in D+ as compared to D- groups.
In a large contemporary cohort, CMV status at the time of HTx was not associated with CAV development. However, there was a significant association between donor CMV seropositivity and reduced short- and long-term survival after HTx. Approaches to mitigate the impact of CMV on posttransplant survival are needed.
The major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction ...(CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice.
C57BL/6 mice (H-2b) donor tracheas were orthotopically transplanted into CBA/J mice (H-2k). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively.
Tracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05 and a reduced submucosal smooth muscle actin (SMA) content SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment.
Receptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.
•Nintedanib improved allogeneic airway immune injury.•Reduced immune cell infiltration after nintedanib treatment.•Nintedanib diminished fibro-proliferative tissue remodelling.
BACKGROUND.Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction (CLAD). The aim of this study was to investigate if platelet inhibition by ...clopidogrel has a functionally relevant influence on the microvascular integrity of orthotopic tracheal allografts as an anatomic basis for the development of CLAD.
METHODS.We orthotopically transplanted C57Bl/6 (H-2) tracheas into CBA.J (H-2) recipients who afterwards received clopidogrel (1 mg/kg). Morphometric analysis was performed by measuring epithelial height in proportion to thickness of the lamina propria (epithelium-lamina propria ratio). Tissue oxygenation was determined using a fluorescence quenching technique, and graft perfusion monitoring was performed by laser Doppler flowmetry and lectin-binding assay. Immunohistochemistry was used for detection of CD31 and inducible nitric oxide synthase while iron deposition was shown with Prussian blue reaction. Quantitative reverse transcription polymerase chain reaction analysis was used for gene expression analysis.
RESULTS.Isografts maintained good oxygenation and perfusion throughout the experiment, while both were drastically reduced in allografts. Treatment with clopidogrel attenuated graft hypoxia and reduced loss of perfusion. Additionally, clopidogrel led to increased epithelium-lamina propria ratio while iron deposition was impaired. Gene expression analysis revealed elevated levels of angiogenic vascular endothelial growth factor in the clopidogrel group. Improved endothelial function was shown by immunohistochemistry (CD31, inducible nitric oxide synthase).
CONCLUSIONS.Continuous administration of clopidogrel significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia. These data demonstrate that clopidogrel ameliorates microvascular injury during acute airway rejection, which is a known predisposing factor for the development of CLAD.
The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study ...was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE
−/−
mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control)
n
= 8,
P
< 0.05. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGFβ were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of ‘de-novo’ atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions.
Objectives
We present our single center experience with Medtronic CoreValve and Evolut R regarding procedural outcome and 3 years follow‐up in patients with degenerated bioprostheses.
Methods
From ...1645 patients who underwent transfemoral TAVI at our institution between February 2009 and December 2016, 37 patients with degenerated bioprosthesis were treated with Medtronic CoreValve/Evolut R. All data concerning baseline characteristic, procedural outcomes and follow‐up were entered into a dedicated database.
Results
Mean age was 83.9 ± 4.4 years and patients showed an average logistic EuroSCORE of 33.2 ± 16.7%. Successful ViV deployment was achieved in all cases, a permanent pacemaker was implanted in 16.2%, no periinterventional stroke and no coronary obstruction occurred. Mortality at 30 days was 2.7%, at 1‐year follow‐up 5.7% and at three years 13.5%. Depending on bioprosthesis size <23 mm versus ≥23 mm echocardiographic mean gradients post implantation were significantly higher in the smaller bioprostheses, 22.8 mmHg ± 9.4 mmHg versus 15.1 ± 7.1, P = 0.013.
Conclusion
ViV‐TAVI with CoreValve/R is demonstrated to be safe and effective in terms of no coronary obstruction and very low mortality up to 3 years despite slightly higher mean transprosthetic gradients especially in very small bioprostheses.
Background For nonagenarians with symptomatic severe aortic stenosis transcatheter aortic valve implantation (TAVI) has become a feasible therapeutic option. Therefore, the aim of this study was to ...evaluate the procedural outcomes and mid-term follow-up in this patient group and compare this to octogenarians. Methods From 1359 patients who underwent TAVI at our institution between March 2009 and February 2016, 82 patients were nonagenarians and 912 were octogenarians. In nonagenarians, mean age was 91.9 ± 1.4 years and compared to octogenarians showed a significantly higher logistic EuroScore (27.7 ± 14.8% vs. 23.1 ± 14.4, p = 0.005) and STS Score (8.5 ± 4.8% vs. 6.3 ± 6.7, p = 0.001). Results There were no significant differences with regard to stroke rate, pacemaker implantation rate and major vascular complications between the two groups. Thirty-day mortality was 9.8% in nonagenarians and 4.1% in octogenarians (p = 0.04). At one year, all-cause mortality increased to 30.9% vs. 18.6% (n.s.). Conclusion Nonagenarians showed an increased periprocedural mortality during TAVI and higher mortality in follow-up compared to octogenarians. Age alone is not a predictive factor but indication for treatment should be carefully evaluated by the heart team on an individual basis.
Abstract
OBJECTIVES
Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction. Previous studies have suggested T-cell mediated proliferation and ...microvascular changes in experimental small airways models as potential therapeutic targets. The aim of this study was to assess microvascular changes in murine orthotopic tracheal allografts after treatment with everolimus alone or in combination with clopidogrel.
METHODS
C57Bl/6 (H-2b) donor tracheas were orthotopically transplanted into CBA (H-2k) recipients. Mice received daily injections of everolimus (0.05 mg/kg) alone or combined with clopidogrel (1 mg/kg). Twenty-eight days after transplantation, ratio of the thickness of tracheal epithelium and lamina propria was measured as an indicator for chronic rejection. Additionally, graft oxygenation and graft perfusion were detected on postoperative days 4, 10 and 28. Quantitative reverse transcription polymerase chain reaction analysis was used for gene expression analysis.
RESULTS
While syngeneic grafts showed a stable tissue pO2 and undisturbed microvascular perfusion, rejecting allografts had a drastic decline in both parameters as well as a flattened epithelium and an increased thickness of the lamina propria. Treatment with everolimus reduced allogeneic fibroproliferation, but had no protective effects on the microvasculature; polymerase chain reaction analysis indicated hypoxic stress and inflammation. Combining everolimus with clopidogrel improved microvascular integrity in the tracheal grafts, but had no synergistic effect in preventing obliterative bronchiolitis development.
CONCLUSIONS
These data demonstrate that the ability of everolimus to reduce the development of post-transplant obliterative bronchiolitis is not caused by microvascular protection and has no synergistic effects with clopidogrel in acute airway rejection.
It was previously shown that the combination of clopidogrel and everolimus reduced the development of transplant arteriosclerosis. The aim of this study was to investigate whether delayed onset of ...treatment, similar to the clinical situation after heart transplantation, inhibits progression of transplant arteriosclerosis.
Fully allogeneic C57BL/6 (H2-b) donor aortas were transplanted into CBA.J (H2-k) recipients treated with clopidogrel and everolimus alone or in combination starting on Days 1, 7 or 14. Grafts were analysed by histology and alloantibodies were detected by fluorescence activated cell sorting after transplantation.
Delayed platelet inhibition with clopidogrel reduced the development of transplant arteriosclerosis neointima formation (Day 14): 50±4 vs 84±9% (control). The combination of clopidogrel and everolimus almost abolished formation of transplant arteriosclerosis when therapy was started on Day 1 neointima formation (Day 1): 14±5 vs 84±9% (control) and also showed a remarkable reduction in both delayed treatment groups neointima formation (Day 7): 24±7 vs 84±9% (control); neointima formation (Day 14): 28±11 vs 84±9% (control). Platelet inhibition alone and in combination with everolimus resulted in reduced alloantibody production.
These results demonstrate that delayed treatment with clopidogrel and everolimus-representative of a clinical setting-prevents the progression of transplant arteriosclerosis and impairs humoral immunity in this experimental model.
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