The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no ...uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.
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.
New-onset conduction disturbances still represent a considerable problem after transcatheter aortic valve implantation (TAVI). The aim of this study was to identify calcification patterns with an ...elevated risk for permanent pacemaker implantation (PPI) after TAVI and investigate underlying mechanisms in an ex vivo setting.
One hundred and sixty-two patients who underwent TAVI with the Edwards SAPIEN XT
or Medtronic CoreValve
at our institution were analysed. The calcium load of the device landing zone was quantified with 3mensio
, and calcium patterns with an elevated risk for PPI were identified. Ex vivo simulations of balloon valvuloplasty were performed in 3D-printed silicone annuli of patients matching the identified risk profile. Patients with a calcium load of the left coronary cusp (LCC) above 209 mm
had a higher rate of PPI than patients below this threshold (16.7 vs. 2.6%, P = 0.003). Multivariate regression revealed pre-existing right bundle branch block (RBBB) and increased LCC calcification as independent predictors for PPI. Simulation of the TAVI procedure in a silicone annulus revealed an off-centreline shift of the valvuloplasty balloon and transcatheter heart valve away from the LCC towards the commissure between right- and non-coronary cusp.
Pre-existing RBBB and elevated LCC calcification were identified as independent predictors for PPI. These two risk factors enabled us to distinguish between patients according to their risk for PPI after TAVI. Ex vivo simulations suggested an off-centreline shift of the balloon as a possible explanation.
Evaluation of the impact of the sheath diameter on vascular complications and mortality in transfemoral aortic valve implantation.
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.
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.
The difference in sheath diameter had no effect on either incidence or severity of vascular complications. There was no impact on mortality either.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
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.
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.
A positive family history is a major independent risk factor for atherosclerosis, and genetic variation is an important aspect of cardiovascular disease research. We identified a heterozygous ...missense variant p.L245P in the MMP10 gene in two families with premature myocardial infarction using whole-exome sequencing. The aim of this study was to investigate the consequences of this variant using in-silico and functional in-vitro assays. Molecular dynamics simulations were used to analyze protein interactions, calculate free binding energy, and measure the volume of the substrate-binding cleft of MMP10-TIMP1 models. The p.L245P variant showed an altered protein surface, different intra- and intermolecular interactions of MMP10-TIMP1, a lower total free binding energy between MMP10-TIMP1, and a volume-minimized substrate-binding cleft of MMP10 compared to the wild-type. For the functional assays, human THP-1 cells were transfected with plasmids containing MMP10 cDNA carrying the p.L245P and wild-type variant and differentiated into macrophages. Macrophage adhesion and migration assays were then conducted, and pro-inflammatory chemokine levels were evaluated. The p.L245P variant led to macrophages that were more adherent, less migratory, and secreted higher levels of the pro-inflammatory chemokines CXCL1 and CXCL8 than wild-type macrophages. Thus, the p.L245P variant in MMP10 may influence the pathogenesis of atherosclerosis in families with premature myocardial infarction by altering protein - protein interactions, macrophage adhesion and migration, and expression of pro-inflammatory chemokines, which may increase plaque rupture. These results could contribute to the development of selective MMP10 inhibitors and reduce the risk of atherosclerosis in families with a history of premature myocardial infarction.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
OBJECTIVES:
Surgical aortic valve replacement (sAVR) is coming under close scrutiny with the recent upswing in the use of less invasive approaches. The aim of this analysis was to identify ...current trends in patient selection, procedural characteristics and outcomes after sAVR in Germany.
METHODS:
We analysed data from 42 776 patients included in the German Aortic Valve Registry who underwent sAVR with and without coronary artery bypass surgery (CABG) between 2011 and 2015. Baseline, procedural and short-term outcome parameters were analysed.
RESULTS:
Of all registered patients, 26 618 (62.2%) underwent isolated sAVR and 16 158 (37.8%) sAVR + CABG. The median age was 72 years, and the median Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) was 2.3%. From 2011 to 2015, there was a decline in STS PROM (2.4–2.2%, P < 0.001) and a decline in risk factors, such as pulmonary hypertension (9.1–3.2%, P < 0.001), occlusive arterial disease (19.6–17.7%, P = 0.003), mitral regurgitation ≥2° (10.6–7.6%, P < 0.001) and New York Heart Association Class III/IV (65.3–59.2%, P < 0.001). In-hospital mortality was 2.3%, 1.3% had disabling stroke, 0.4% residual aortic regurgitation ≥2°, and the incidence of new-onset pacemaker/implantable cardioverter–defibrillator implantation was 3.9%. There was an increase in the use of biological valves in patients <65 years (50.1–65.7%, P < 0.001), and the proportion of rapid deployment valves increased significantly (1.5–8.4%, P < 0.001) over the investigated time period.
CONCLUSIONS:
Both isolated sAVR as well as sAVR + CABG resulted in excellent in-hospital outcomes based on >42 000 patients treated between 2011 and 2015. The implementation of alternative treatment strategies has resulted in palpable changes in patient and device selection.
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.
PDF
