Nintedanib reduces alloimmune-induced chronic airway changes in murine tracheal allografts.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cytomegalovirus Donor Seropositivity Negatively Affects Survival After Heart Transplantation.

BACKGROUND: 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. METHODS: 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-). RESULTS: 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. CONCLUSIONS: 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.

Direct Impact of Human Platelets on the Development of Transplant Arteriosclerosis.

BACKGROUND: Platelets play an important role in the pathogenesis of inflammatory and proliferative vascular changes. The aim of this study was to investigate whether human platelets are able to induce transplant arteriosclerosis in a humanized C57/Bl6-Rag2-/-γc-/- mouse xenograft model. METHODS: Nonactivated and in vitro-activated human platelets were analyzed and phenotyped for surface markers by flow cytometry. Side branches of human mammary arteries were implanted into the infrarenal aorta of recipients, followed by daily application of human platelets and histological analyzed on day 30 after transplantation. RESULTS: Human platelets collected by apheresis had low levels of platelet activation markers. However, after in vitro activation, expression was markedly increased. Sixty minutes after injection in recipient mice, nonactivated human platelets become significantly activated. Increased adhesion of platelets to the vascular endothelium was detected by in vivo fluorescence microscopy. After intravenous injection of nonactivated or activated platelets, human xenografts showed pronounced intimal proliferation. Immunohistological analysis showed that the group treated with activated human platelets exhibited significantly increased intragraft protein expression of intracellular adhesion molecule-1 and platelet-derived growth factor receptor beta and smooth muscle cell migration into the neointima. CONCLUSIONS: These data demonstrate that an isolated daily application of both in vivo- and in vitro-activated human platelets results in the development of transplant arteriosclerosis in a humanized mouse transplantation model.

Microvasculature in murine tracheal allografts after combined therapy with clopidogrel and everolimus.

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.

Platelets and Immune Responses During Thromboinflammation.

Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases. FXII of the intrinsic pathway connects platelet activation with the coagulation cascade during immune reactions. It can activate the contact system thereby either creating an inflammatory state or accelerating inflammation. Recent insights into platelet biology could show that platelets are equipped with complement receptors. Platelets are important for tissue remodeling after injury has been inflicted to the endothelial barrier and to the subendothelial tissue. Thus, platelets are increasingly recognized as more than just cells relevant for bleeding arrest. Future insights into platelet biology are to be expected. This research will potentially offer novel opportunities for therapeutic intervention in diseases featuring platelet abundance.

Preservation of Microvascular Integrity in Murine Orthotopic Tracheal Allografts by Clopidogrel.

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.

Outcomes of transcatheter mitral valve replacement for degenerated bioprostheses, failed annuloplasty rings, and mitral annular calcification.

Aims: We sought to evaluate the outcomes of transcatheter mitral valve replacement (TMVR) for patients with degenerated bioprostheses [valve-in-valve (ViV)], failed annuloplasty rings [valve-in-ring (ViR)], and severe mitral annular calcification [valve-in-mitral annular calcification (ViMAC)]. Methods and results: From the TMVR multicentre registry, procedural and clinical outcomes of ViV, ViR, and ViMAC were compared according to Mitral Valve Academic Research Consortium (MVARC) criteria. A total of 521 patients with mean Society of Thoracic Surgeons score of 9.0 ± 7.0% underwent TMVR (322 patients with ViV, 141 with ViR, and 58 with ViMAC). Trans-septal access and the Sapien valves were used in 39.5% and 90.0%, respectively. Overall technical success was excellent at 87.1%. However, left ventricular outflow tract obstruction occurred more frequently after ViMAC compared with ViR and ViV (39.7% vs. 5.0% vs. 2.2%; P < 0.001), whereas second valve implantation was more frequent in ViR compared with ViMAC and ViV (12.1% vs. 5.2% vs. 2.5%; P < 0.001). Accordingly, technical success rate was higher after ViV compared with ViR and ViMAC (94.4% vs. 80.9% vs. 62.1%; P < 0.001). Compared with ViMAC and ViV groups, ViR group had more frequent post-procedural mitral regurgitation ≥moderate (18.4% vs. 13.8% vs. 5.6%; P < 0.001) and subsequent paravalvular leak closure (7.8% vs. 0.0% vs. 2.2%; P = 0.006). All-cause mortality was higher after ViMAC compared with ViR and ViV at 30 days (34.5% vs. 9.9% vs. 6.2%; log-rank P < 0.001) and 1 year (62.8% vs. 30.6% vs. 14.0%; log-rank P < 0.001). On multivariable analysis, patients with failed annuloplasty rings and severe MAC were at increased risk of mortality after TMVR [ViR vs. ViV, hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.27-3.12; P = 0.003; ViMAC vs. ViV, HR 5.29, 95% CI 3.29-8.51; P < 0.001]. Conclusion: The TMVR provided excellent outcomes for patients with degenerated bioprostheses despite high surgical risk. However, ViR and ViMAC were associated with higher rates of adverse events and mid-term mortality compared with ViV.

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts.

BACKGROUND: Nintedanib is a small molecule tyrosine kinase inhibitor that blocks the action of the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR) and the fibroblast growth factor receptor. All of these receptors have been shown to be involved in the development of cardiac allograft vasculopathy (CAV) after heart transplantation. We therefore hypothesized that blocking these tyrosine kinase receptors with nintedanib could prevent CAV. METHODS: CBA/JRj (H2k) mice underwent an abdominal aortic transplantation with a graft derived from fully allogeneic C57BL/6JRj (H2b) mice. Nintedanib was given daily from the first day after transplantation until harvest on day 14 for polymerase chain reaction analysis of intragraft cytokine expression or harvest on day 30 for histological analysis of the graft. RESULTS: Nintedanib treatment resulted in significantly reduced neointima formation in the aortic graft compared with untreated control allografts. Interestingly, the immigration of smooth muscle cells into the neointima was markedly reduced while graft infiltrating macrophages and T cells were not altered in nintedanib-treated animals. The expression of the growth factor PDGF was significantly reduced in the nintedanib group going along with a distinctly reduced expression of the corresponding receptors PDGFR α and -ß. CONCLUSIONS: Treatment with nintedanib caused a significant reduction of CAV development after aortic transplantation in mice. We hypothesize the attenuated neointima formation in nintedanib-treated animals to be mediated by a direct inhibition of intimal smooth muscle cell proliferation via reduced expression of PDGF and the appropriate receptors PDGFR α + ß.

Effects of different serotonin receptor subtype antagonists on the development of cardiac allograft vasculopathy in murine aortic allografts.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. METHODS: CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. RESULTS: Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. CONCLUSION: Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.

Valve-in-valve transcatheter aortic valve implantation with CoreValve/Evolut R© for degenerated small versus bigger bioprostheses.

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.

Transcatheter Aortic Valve Implantation in Nonagenarians: Procedural Outcome and Mid-Term Results.

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±1.4years 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 1 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.

AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome.

Marfan syndrome is characterized by high expression of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMCs) associated with medial elastolysis and aortic root aneurysm. We aimed to reduce aortic elastolysis through decrease of MMP expression with decoy oligodeoxynucleotides (dODNs) neutralizing the transcription factor activating factor-1 (AP-1). AP-1 abundance in nuclear extracts as well as MMP-2 and MMP-9 expression were significantly increased in isolated mAoSMC of mgR/mgR Marfan mice compared to wild-type cells. Exposure to AP-1 neutralizing dODNs resulted in a significant reduction of basal and interleukin-1ß-stimulated MMP expression and activity in mAoSMCs. Moreover, increased migration and formation of superoxide radical anions was substantially decreased in mAoSMCs by AP-1 dODN treatment. Aortic grafts from donor Marfan mice were treated with AP-1- dODN ex vivo and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Pretreatment of aortic grafts with AP-1 dODN led to reduced elastolysis, macrophage infiltration, and MMP activity. Permeability of the endothelial monolayer was increased for dODN in mgR/mgR aortae with observed loss of tight junction proteins ZO-1 and occludin, enabling dODN to reach the tunica media. Targeting AP-1 activity offers a new potential strategy to treat the vascular phenotype associated with Marfan syndrome.

Transcatheter Aortic Valve Replacement in Pure Native Aortic Valve Regurgitation.

BACKGROUND: Limited data exist about safety and efficacy of transcatheter aortic valve replacement (TAVR) in patients with pure native aortic regurgitation (AR). OBJECTIVES: This study sought to compare the outcomes of TAVR with early- and new-generation devices in symptomatic patients with pure native AR. METHODS: From the pure native AR TAVR multicenter registry, procedural and clinical outcomes were assessed according to VARC-2 criteria and compared between early- and new-generation devices. RESULTS: A total of 331 patients with a mean STS score of 6.7 ± 6.7 underwent TAVR. The early- and new-generation devices were used in 119 patients (36.0%) and 212 patients (64.0%), respectively. STS score tended to be lower in the new-generation device group (6.2 ± 6.7 vs. 7.6 ± 6.7; p = 0.08), but transfemoral access was more frequently used in the early-generation device group (87.4% vs. 60.8%; p < 0.001). Compared with the early-generation devices, the new-generation devices were associated with a significantly higher device success rate (81.1% vs. 61.3%; p < 0.001) due to lower rates of second valve implantation (12.7% vs. 24.4%; p = 0.007) and post-procedural AR ≥ moderate (4.2% vs. 18.8%; p < 0.001). There were no significant differences in major 30-day endpoints between the 2 groups. The cumulative rates of all-cause and cardiovascular death at 1-year follow-up were 24.1% and 15.6%, respectively. The 1-year all-cause mortality rate was significantly higher in the patients with post-procedural AR ≥ moderate compared with those with post-procedural AR ≤ mild (46.1% vs. 21.8%; log-rank p = 0.001). On multivariable analysis, post-procedural AR ≥ moderate was independently associated with 1-year all-cause mortality (hazard ratio: 2.85; 95% confidence interval: 1.52 to 5.35; p = 0.001). CONCLUSIONS: Compared with the early-generation devices, TAVR using the new-generation devices was associated with improved procedural outcomes in treating patients with pure native AR. In patients with pure native AR, significant post-procedural AR was independently associated with increased mortality.

Transcatheter Mitral Valve Replacement for Degenerated Bioprosthetic Valves and Failed Annuloplasty Rings.

BACKGROUND: Limited data exist regarding transcatheter mitral valve replacement (TMVR) for patients with failed mitral valve replacement and repair. OBJECTIVES: This study sought to evaluate the outcomes of TMVR in patients with failed mitral bioprosthetic valves (valve-in-valve [ViV]) and annuloplasty rings (valve-in-ring [ViR]). METHODS: From the TMVR multicenter registry, procedural and clinical outcomes of mitral ViV and ViR were compared according to Mitral Valve Academic Research Consortium criteria. RESULTS: A total of 248 patients with mean Society of Thoracic Surgeons score of 8.9 ± 6.8% underwent TMVR. Transseptal access and the balloon-expandable valve were used in 33.1% and 89.9%, respectively. Compared with 176 patients undergoing ViV, 72 patients undergoing ViR had lower left ventricular ejection fraction (45.6 ± 17.4% vs. 55.3 ± 11.1%; p < 0.001). Overall technical and device success rates were acceptable, at 92.3% and 85.5%, respectively. However, compared with the ViV group, the ViR group had lower technical success (83.3% vs. 96.0%; p = 0.001) due to more frequent second valve implantation (11.1% vs. 2.8%; p = 0.008), and lower device success (76.4% vs. 89.2%; p = 0.009) due to more frequent reintervention (16.7% vs. 7.4%; p = 0.03). Mean mitral valve gradients were similar between groups (6.4 ± 2.3 mm Hg vs. 5.8 ± 2.7 mm Hg; p = 0.17), whereas the ViR group had more frequent post-procedural mitral regurgitation moderate or higher (19.4% vs. 6.8%; p = 0.003). Furthermore, the ViR group had more frequent life-threatening bleeding (8.3% vs. 2.3%; p = 0.03), acute kidney injury (11.1% vs. 4.0%; p = 0.03), and subsequent lower procedural success (58.3% vs. 79.5%; p = 0.001). The 1-year all-cause mortality rate was significantly higher in the ViR group compared with the ViV group (28.7% vs. 12.6%; log-rank test, p = 0.01). On multivariable analysis, failed annuloplasty ring was independently associated with all-cause mortality (hazard ratio: 2.70; 95% confidence interval: 1.34 to 5.43; p = 0.005). CONCLUSIONS: The TMVR procedure provided acceptable outcomes in high-risk patients with degenerated bioprostheses or failed annuloplasty rings, but mitral ViR was associated with higher rates of procedural complications and mid-term mortality compared with mitral ViV.

Impact of sheath diameter of different sheath types on vascular complications and mortality in transfemoral TAVI approaches using the Proglide closure device.

OBJECTIVE: Evaluation of the impact of the sheath diameter on vascular complications and mortality in transfemoral aortic valve implantation. METHOD: Between 2012 and 2014, 183 patients underwent the procedure using a sheath diameter of 18-24 F. This collective was divided into two groups: group 1, with a sheath diameter of 18F (G1, n = 94), consisted of patients with 18F Medtronic Sentrant and 18 F Direct Flow sheaths, and group 2 with a sheath diameter of 19-24 F (G2, n = 89) consisted of patients with Edwards expandable e-sheath and Solopath sheaths. Perclose-Proglide® was used as a closure device in all patients. RESULTS: G1 had significantly more female patients (64.9% vs. 46.1% in G2, p = 0.01) and the average BMI was lower (26 ± 4.5% vs. 27.4 ± 4.7%, p = 0.03). There was no significant difference in the incidence of major and minor vascular complications (G1: 12.8% vs. G2: 12.4%, p = 0.9). 30-day mortality was similar in both groups (G1: 6.4 ± 2.5% [95% CI: 0.88-0.98], G2: 3.7 ± 1.9% [95% CI: 0.92-0.99]. The Kaplan Meier analysis of survival revealed no significant differences either. CONCLUSION: The difference in sheath diameter had no effect on either incidence or severity of vascular complications. There was no impact on mortality either.

Outcomes in Transcatheter Aortic Valve Replacement for Bicuspid Versus Tricuspid Aortic Valve Stenosis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is being increasingly performed in patients with bicuspid aortic valve stenosis (AS). OBJECTIVES: This study sought to compare the procedural and clinical outcomes in patients with bicuspid versus tricuspid AS from the Bicuspid AS TAVR multicenter registry. METHODS: Outcomes of 561 patients with bicuspid AS and 4,546 patients with tricuspid AS were compared after propensity score matching, assembling 546 pairs of patients with similar baseline characteristics. Procedural and clinical outcomes were recorded according to Valve Academic Research Consortium-2 criteria. RESULTS: Compared with patients with tricuspid AS, patients with bicuspid AS had more frequent conversion to surgery (2.0% vs. 0.2%; p = 0.006) and a significantly lower device success rate (85.3% vs. 91.4%; p = 0.002). Early-generation devices were implanted in 320 patients with bicuspid and 321 patients with tricuspid AS, whereas new-generation devices were implanted in 226 and 225 patients with bicuspid and tricuspid AS, respectively. Within the group receiving early-generation devices, bicuspid AS had more frequent aortic root injury (4.5% vs. 0.0%; p = 0.015) when receiving the balloon-expanding device, and moderate-to-severe paravalvular leak (19.4% vs. 10.5%; p = 0.02) when receiving the self-expanding device. Among patients with new-generation devices, however, procedural results were comparable across different prostheses. The cumulative all-cause mortality rates at 2 years were comparable between bicuspid and tricuspid AS (17.2% vs. 19.4%; p = 0.28). CONCLUSIONS: Compared with tricuspid AS, TAVR in bicuspid AS was associated with a similar prognosis, but lower device success rate. Procedural differences were observed in patients treated with the early-generation devices, whereas no differences were observed with the new-generation devices.

Mechanical Circulatory Support: Heart Failure Therapy "in Motion".

Because the first generation of pulsatile-flow devices was primarily used to bridge the sickest patients to transplantation (bridge-to-transplant therapy), the current generation of continuous-flow ventricular assist devices qualifies for destination therapy for patients with advanced heart failure who are ineligible for transplantation. The first-generation devices were associated with frequent adverse events, limited mechanical durability, and patient discomfort due device size. In contrast, second-generation continuous-flow devices are smaller, more quiet, and durable, thus resulting in less complications and significantly improved survival rates. Heart transplantation remains an option for a limited number of patients only, and this fact has also triggered the discussion about the optimal timing for device implantation. The increasing use of continuous-flow devices has resulted in new challenges, such as adverse events during long-term support, and high hospital readmission rates. In addition, there are a number of device-related complications including mechanical problems such as device thrombosis, percutaneous driveline damage, as well as conditions such as hemolysis, infection, and cerebrovascular accidents. This review provides an overview of the evolution of mechanical circulatory support systems from bridge to transplantation to destination therapy including technological advances and clinical improvements in long-term patient survival and quality of life. In addition, recent changes in device implant strategies and current trials are reviewed and discussed. A brief glimpse into the future of mechanical circulatory support therapy will summarize the innovations that may soon enter clinical practice.

Reduction of obliterative bronchiolitis (OB) by prolyl-hydroxylase-inhibitors activating hypoxia-inducible transcription factors in an experimental mouse model.

BACKGROUND: Obliterative bronchiolitis (OB) is the major limiting factor for long-term survival after lung transplantation. As previously shown, donor treatment with a PHD-inhibitor activating hypoxia-inducible transcription factors (HIFs) prevents graft injury both in an allogenic kidney and aortic allograft transplant model. The aim of this study was to investigate the effect of HIF activation with a PHD-inhibitor on the development of OB. METHODS: Fully MHC-mismatched C57BL/6 (H-2b) donor tracheas were orthotopically transplanted into CBA/J (H-2k) recipients. Donor animals received a single dose of PHD-inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) (40mg/kg i.p.) or vehicle control 4h before transplantation. Transplanted tracheas were harvested 14 or 30days after transplantation and were analyzed by histology, by immunofluorescence and by rtPCR for mRNA expression. RESULTS: Donor pre-conditioning with ICA resulted in HIF accumulation and induction of HIF target genes: HO-1, VEGF, MIF, TGFß, and EpoR, which persisted during different times of ischemia. Grafts of vehicle treated controls showed substantially more luminal obliteration on postoperative day 30 in contrast to groups pre-treated with ICA [luminal obliteration 29.2±5% (ICA) vs. 36.7±8% (control), p<0.01]. We found significantly lower expression of TNFα, PDGFß, MCP-1, E-selectin, and ICAM-1 14days after ICA premedication. In addition ICA pre-treated groups revealed decreased T-cell and macrophage infiltration in tracheal grafts on days 30 after transplantation (p<0.05). CONCLUSION: Pre-treatment with ICA effectively reduced obliterative bronchiolitis. Our data suggest that activation of hypoxia-inducible transcription factors (HIFs) and thereby adaptation to low oxygen prevents the development of OB and allograft injury. Pharmaceutical inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves further clinical evaluation.