Midterm clinical outcome following Edwards SAPIEN or Medtronic Corevalve transcatheter aortic valve implantation (TAVI): Results of the Belgian TAVI registry.

OBJECTIVE: To assess midterm (3 years) clinical outcomes of transcatheter aortic valve implantation (TAVI) in Belgium using the Edwards SAPIEN valve or the Medtronic CoreValve transcatheter heart valve (THV). BACKGROUND: Medium and long term follow-up data of both THVs are still relatively scarce, although of great clinical relevance for a relatively new but rapidly expanding treatment modality. Therefore, reporting mid- and long term clinical outcome data, coming from large "real world" national registries, remains contributive. METHODS: Between December 2007 and March 2012, 861 "real world" patients who were not candidates for surgical aortic valve replacement as decided by the local heart teams, underwent TAVI at 23 sites. Eleven sites exclusively used SAPIEN THV (n = 460), while 12 exclusively used CoreValve THV (n = 401). Differences in clinical outcomes by valve system were assessed, according to access route and baseline EuroSCORE risk profile (<10%: low, 10-20%: intermediate and >20%: high risk). RESULTS: Overall cumulative survival at 3 years was 51% for SAPIEN vs. 60% for CoreValve (P = 0.021). In transfemorally treated patients, SAPIEN and CoreValve had similar survival at 3 years for each of the baseline EuroSCORE cohorts (low risk: 72% vs. 76%, P = 0.45; intermediate risk: 62% vs. 59%, P = 0.94; high risk: 48% vs. 53%, P = 0.65). CONCLUSION: Cumulative midterm 3 year survival after transfemoral TAVI in "real world" patients refused for surgery with similar baseline EuroSCORE risk profile is not different between SAPIEN or CoreValve.

Resolute and Xience V polymer-based drug-eluting stents compared in an atherosclerotic rabbit double injury model.

AIM: To evaluate differences in strut coverage, inflammation and endothelialization between two second-generation polymer-based drug-eluting stents (DES) in an atherosclerotic rabbit double-injury iliac artery model at 28 days follow-up. METHODS AND RESULTS: Rabbits with induced atheroma received bilateral iliac artery stents: everolimus-eluting stent (Xience V EES; Abbott Vascular), zotarolimus-eluting stent (Resolute ZES; Medtronic CardioVascular), or bare-metal stent (BMS; MultiLink Vision; Abbott Vascular). After 28 days, total neointimal coverage examined by scanning electron microscopy was >98% for all three stent types. Neointimal thickness above stent struts was decreased by 50% in Xience V EES (0.06 ± 0.01 mm; P = 0.00001) compared with BMS (0.15 ± 0.03 mm) and Resolute ZES (0.12 ± 0.04 mm). Luminal area was largest for Xience V EES (3.79 ± 0.33 mm(2) ; P = 0.0003 for Xience V EES vs. BMS), followed by Resolute ZES (3.46 ± 0.45 mm(2) ; P = 0.083 for Resolute ZES vs. BMS) and BMS (3.07 ± 0.53 mm(2) ). Percentage area stenosis was smallest for Xience V EES (17.23 ± 3.64%; P = 0.00001), while BMS (30.25 ± 7.48%) and Resolute ZES (30.79 ± 7.15%) did not differ. Endothelial monolayer regrowth was significantly lower in Resolute ZES (65 ± 13%) versus BMS (79 ± 11%; P = 0.004). There was no difference between Xience V EES (74 ± 10%) and BMS. Xience V EES was further associated with a lower number of inflammatory cells surrounding the stent struts (7 ± 2 per strut) in comparison to Resolute ZES (15 ± 6; P = 0.0001) and BMS (17 ± 9; P = 0.0005). CONCLUSION: In this atherosclerotic rabbit model, Xience V EES suppressed neointimal thickening better, with normal endothelial regrowth as compared with BMS, and less strut-induced inflammation.

Decreased numbers of peripheral blood dendritic cells in patients with coronary artery disease are associated with diminished plasma Flt3 ligand levels and impaired plasmacytoid dendritic cell function.

We investigated whether activation of circulating DCs (dendritic cells) or levels of Flt3L (FMS-like tyrosine kinase 3 ligand) and GM-CSF (granulocyte/macrophage colony-stimulating factor), haematopoietic growth factors important for DC differentiation, could account for reduced blood DC numbers in CAD (coronary artery disease) patients. Concentrations of Flt3L and GM-CSF were measured in plasma from CAD patients (n = 15) and controls (n = 12). Frequency and phenotype of mDCs (myeloid dendritic cells) and pDCs (plasmacytoid dendritic cells) were analysed by multicolour flow cytometry in fresh blood, and after overnight incubation with TLR (Toll-like receptor)-4 or -7 ligands LPS (lipopolysaccharide) or IQ (imiquimod). DC function was measured by IL (interleukin)-12 and IFN (interferon)-α secretion. Circulating numbers of CD11c+ mDCs and CD123+ pDCs and frequencies of CD86+ and CCR-7+ (CC chemokine receptor type 7) mDCs, but not pDCs, were declined in CAD. In addition, plasma Flt3L, but not GM-CSF, was lower in patients and positively correlated with blood DC counts. In response to LPS, mDCs up-regulated CD83 and CD86, but CCR-7 expression and IL-12 secretion remained unchanged, similarly in patients and controls. Conversely, pDCs from patients had lower CD83 and CCR-7 expression after overnight incubation and had a weaker IQ-induced up-regulation of CD83 and IFN-α secretion. In conclusion, our results suggest that reduced blood DC counts in CAD are, at least partly, due to impaired DC differentiation from bone marrow progenitors. Decreased levels of mDCs are presumably also explained by activation and subsequent migration to atherosclerotic plaques or lymph nodes. Although mDCs are functioning normally, pDCs from patients appeared to be both numerically and functionally impaired.

Dendritic cells in human atherosclerosis: from circulation to atherosclerotic plaques.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease with atherosclerotic plaques containing inflammatory infiltrates predominantly consisting of monocytes/macrophages and activated T cells. More recent is the implication of dendritic cells (DCs) in the disease. Since DCs were demonstrated in human arteries in 1995, numerous studies in humans suggest a role for these professional antigen-presenting cells in atherosclerosis. AIM: This paper focuses on the observations made in blood and arteries of patients with atherosclerosis. In principal, flow cytometric analyses show that circulating myeloid (m) and plasmacytoid (p) DCs are diminished in coronary artery disease, while immunohistochemical studies describe increased intimal DC counts with evolving plaque stages. Moreover, mDCs and pDCs appear to behave differently in atherosclerosis. Yet, the origin of plaque DCs and their relationship with blood DCs are unknown. Therefore, several explanations for the observed changes are postulated. In addition, the technical challenges and discrepancies in the research field are discussed. FUTURE: Future studies in humans, in combination with experimental animal studies will unravel mechanisms leading to altered blood and plaque DCs in atherosclerosis. As DCs are crucial for inducing but also dampening immune responses, understanding their life cycle, trafficking and function in atherosclerosis will determine potential use of DCs in antiatherogenic therapies.

Clinical relevance of clopidogrel unresponsiveness during elective coronary stenting: experience with the point-of-care platelet function assay-100 C/ADP.

BACKGROUND: Early identification of nonresponders to clopidogrel may be important in identifying subgroups of patients that might be at risk for future thrombotic events. METHODS: We prospectively assessed postclopidogrel platelet reactivity in 250 consecutive patients scheduled for elective percutaneous coronary intervention (PCI). All patients received dual antiplatelet therapy with 160 mg aspirin and a 300 mg loading dose of clopidogrel >12 hours before PCI. A platelet aggregation test was performed at the time of the intervention using a point-of-care assay, the Platelet Function Assay (PFA-100C/ADP; Dade-Behring, Deerfield, IL). Nonresponders were defined as having a PFA closure time of <71 seconds under dual oral antiplatelet therapy, reflecting normal platelet reactivity. Myonecrosis post-PCI constituted the primary end point and was defined as the release of creatine kinase-MB >1x the upper limit of normal on a sample taken 12 to 24 hours after intervention. The secondary end point was a composite end point of major adverse cardiac events including death, myocardial infarction, and stent thrombosis after 6 months. RESULTS: The PFA closure time was available in 242 patients and ranged from 31 to 300 seconds with a mean value of 147 seconds. Nonresponders represented 7% (17/242) of the cases. Myonecrosis post-PCI occurred in 29 patients (12%) and was more common in nonresponders than in normal responders (29% vs 11%, respectively; P = .03 on multivariate analysis). Major adverse cardiac events at 6 months occurred in 13 patients (1 sudden death possibly related to stent thrombosis and 12 post-PCI myocardial infarctions) and were more common in the nonresponder group (12% vs 5%, respectively; P = .06 on multivariate analysis). CONCLUSIONS: Unresponsiveness to clopidogrel as assessed by the point-of-care test PFA-100C/ADP is an independent major risk factor for thrombotic complications after coronary intervention.

Human C-reactive protein activates monocyte-derived dendritic cells and induces dendritic cell-mediated T-cell activation.

OBJECTIVE: Recent studies proposed a pathogenic role for C-reactive protein (CRP), an independent predictor of cardiovascular disease (CVD), in atherosclerosis. Therefore, we tested whether CRP may modulate dendritic cell (DC) function, because these professional antigen-presenting cells have been implicated in atherogenesis. METHODS AND RESULTS: Human monocyte-derived immature DCs were cultured with human CRP (0 to 60 microg/mL) for 24 hours. Thereafter, activation markers were measured by flow-cytometry and DCs were cocultured with CFSE-labeled lymphocytes to measure T-cell proliferation and interferon (IFN)-gamma secretion after 8 days. Exposure to 60 microg/mL CRP (n=5) induced an activated cell morphology and significant (CD40 increase MFI 5.23+/-0.28, P<0.01 paired t test; CD80 6.18+/-0.51, P<0.01) to modest (CD83 1.38+/-0.17, P<0.05, CCR7 1.60+/-0.29, P=0.05) upregulation of DC activation markers. The expression of CD86 and HLA-DR was high, but not affected. T-lymphocytes incubated with CRP-pulsed DCs displayed increased IFN-gamma secretion and proliferation (P<0.001). DC activation was concentration-dependent and detected from 2 mug/mL CRP; the maximum effect was equivalent to that seen with 0.1 microg/mL lipopolysaccharide (LPS). Polymyxin B abolished the LPS response, without influencing CRP effects. Finally, immunohistochemistry could demonstrate DC/CRP colocalization in human atherosclerotic lesions. CONCLUSIONS: These findings suggest that CRP in plaques or found circulating in CVD patients can influence DC function during atherogenesis.

Stereology: a simplified and more time-efficient method than planimetry for the quantitative analysis of vascular structures in different models of intimal thickening.

OBJECTIVE: Semiautomatic computer-assisted planimetry is currently the standard morphometric technique in models of intimal thickening. We evaluated stereological point counting as an alternative method for the measurement of cross-sectional vascular areas (lumen, intima, and media) by comparing precision, efficiency, and variance components. METHODS: Sections from murine atherosclerotic aorta (n = 21), stented rabbit iliac arteries (n = 30), and porcine coronary arteries (n = 30) were analyzed at two institutes using both techniques. To determine reproducibility, porcine arteries were measured twice. RESULTS: Area measurements showed almost identical means and standard deviations for planimetry and stereology [e.g., intima (mm2): 0.10+/-0.11 vs. 0.12+/-0.12 (mouse), 0.60+/-0.16 vs. 0.60+/-0.15 (rabbit), and 1.92+/-1.52 vs. 1.97+/-1.61 (pig)]. Deming regression and Bland-Altman plots demonstrated a good agreement between both techniques that was not influenced by artery size. Both methods exhibited excellent repeatability, although planimetry (-0.18+/-0.27) was more precise than stereology (-0.17+/-0.47; variance, P < .01, Levene test). In addition, intraoperator variance (error inherent to the technique) was greater for stereology (1.6-15.8% vs. 4.8-33.5%), whereas interoperator variance (error between institutes) was very small for both methods (0.1-0.9% vs. 0.1-1.7%). Indeed, biologic variability was, by far, the most important variance component in all measurements (84-98% vs. 65-95%). Finally, stereology required 20% (mouse; P < .05) to 40% (pig; P < .001) less time to complete analysis. CONCLUSION: The quantification of vascular structures by planimetry and stereology yielded comparable results in all models of intimal thickening, but stereology proved to be less time-consuming. Therefore, study design may dictate the most appropriate choice of technique.

Chlamydia pneumoniae-based atherosclerosis: a smoking gun.

Chronic and acute infectious diseases have been implicated in modifying the risk of atherosclerosis independently or in collaboration with conventional risk factors. During the past two decades, the discussion on microbial agents and atherosclerosis has mainly been centred on Chlamydia pneumoniae. The strongest evidence linking Chlamydia pneumoniae and atherosclerotic disease comes from in vitro experimental studies. In this review, we summarize and critically evaluate the available data of human diagnostic and therapeutic studies on the association of Chlamydia pneumoniae with atherosclerosis. Taking into account the human in vivo data, there is currently insufficient proof linking Chlamydia pneumoniae to atherosclerosis. At present, there are no indications for antibiotic treatment targeted at Chlamydia pneumoniae in the management of atherosclerosis.

Effects of cytochalasin D-eluting stents on intimal hyperplasia in a porcine coronary artery model.

OBJECTIVE: To investigate whether cytochalasin D-eluting stents (CDES) suppress intimal hyperplasia in porcine coronary arteries and to compare the efficacy of paclitaxel and cytochalasin D as inhibitors of vascular smooth muscle cell (SMC) proliferation and platelet aggregation in vitro. METHODS: Rabbit platelet-rich plasma and SMC cultures derived from rabbit aortas were exposed to 10(-8)-10(-5) M cytochalasin D or paclitaxel. Stents directly coated with 2 microg cytochalasin D (low-dose CDES, n=12) and bare stents (n=12) were randomly deployed in the right and left coronary artery of 12 pigs. Six weeks later, neointima was studied using quantitative coronary angiography (QCA) and morphometry. To examine a ten-fold higher dose, polybutyl methacrylate/polyvinyl acetate-coated stents were loaded with 20 microg cytochalasin D. High-dose CDES (n=10) and polymer-only stents (n=11) were deployed in 11 pigs. RESULTS: After 7 days, cytochalasin D (IC(50) 9.9+/-0.4 10(-8) M) and paclitaxel (IC(50) 1.1+/-0.4 10(-8) M) inhibited SMC proliferation in vitro (n=4). In contrast, cytochalasin D (10(-6)-10(-5) M, n=5), but not paclitaxel, attenuated platelet shape change and aggregation induced by ADP. In vivo QCA showed less late lumen loss in low-dose CDES (0.08+/-0.07 vs. 0.32+/-0.08 mm, P=0.05), but morphometry demonstrated only a tendency toward a decreased intimal area. High-dose CDES inhibited both late lumen loss (0.31+/-0.08 vs. 0.91+/-0.06 mm, P<0.01) and intimal area (1.57+/-0.20 vs. 2.46+/-0.22 mm(2), P<0.01). Immunohistochemistry revealed that CDES suppressed peri-strut macrophage recruitment (CD68, P=0.04) and cell proliferation (Ki67, P=0.03) as compared to polymer-only stents without interfering with endothelial cell recovery or the density of alpha-SMC actin staining. Thromboses or edge effects were not observed in either study. CONCLUSIONS: CDES inhibited in-stent hyperplasia. The reduction (39%) with 20 mug CDES was equivalent to that reported for paclitaxel-eluting stents in pigs. Interference with platelet aggregation, SMC migration, SMC proliferation, and leukocyte recruitment could contribute to the benefit. The data indicate that targeting of actin microfilaments has a potential to suppress in-stent restenosis.

Feasibility of tissue magnetic resonance imaging: a pilot study in comparison with tissue Doppler imaging and invasive measurement.

OBJECTIVES: This research was intended to determine the feasibility of tissue magnetic resonance (MR) imaging in comparison with tissue Doppler imaging and its potential implications for the estimation of filling pressure, in comparison with invasive measurement. BACKGROUND: Evaluation of diastolic function using MR imaging is commonly confined to the study of transmitral flow. However, transmitral flow is unreliable for the estimation of left ventricular (LV) filling pressures in hypertrophy and normal systolic function. Normalizing early mitral velocity (E) for the influence of myocardial relaxation by combining E with early diastolic mitral septal tissue velocity (Ea) provides better Doppler estimates of filling pressures. METHODS: Eighteen patients with hypertensive heart disease (LV mass index: 114 +/- 21 g/m(2)), absence of valvular regurgitation, and with normal or mildly reduced systolic function (LV ejection fraction: 57.6 +/- 6.5%) referred for cardiac catheterization, underwent consecutive measurement of mitral flow and septal tissue velocities with phase-contrast MR and Doppler. These data were compared with mean pulmonary capillary wedge pressure (PCWP). RESULTS: There was a strong relation between MR (11.6 +/- 4.3) and Doppler-assessed (12.1 +/- 3.5) E/Ea (95% confidence interval of -1.5 to 0.5) (r = 0.89, p < 0.0001). In addition, E/Ea related strongly to invasively measured PCWP (MR: r = 0.80, p < 0.0001 and Doppler: r = 0.85, p < 0.0001). CONCLUSIONS: Tissue MR imaging is a feasible method to assess Ea. Combining E and Ea allowed similar estimation of filling pressure by MR and Doppler, in good agreement with invasive measurement. The potential confounding effect of valvular regurgitation needs further study.

Relation of B-type natriuretic peptide early after acute myocardial infarction to left ventricular diastolic function and extent of myocardial damage determined by magnetic resonance imaging.

Early after acute myocardial infarction, the relation between plasma B-type natriuretic peptide (BNP) and extent of myocardial scar formation and diastolic dysfunction remains unclear. In 32 consecutive patients early (5 +/- 3 days) after a first acute myocardial infarction, delayed contrast-enhanced magnetic resonance (MR) imaging was performed to define myocardial scar. Diastolic function was assessed using phase-contrast MR measurements of mitral flow and septal tissue velocities (tissue MR imaging) to estimate left ventricular (LV) filling pressures. MR study was immediately followed by BNP measurement. BNP related to LV ejection fraction (r = -0.52, p = 0.002), extent of myocardial scar (percent delayed hyperenhancement of LV mass, r = 0.49, p = 0.005; transmural index, r = 0.58, p <0.001), and estimated LV filling pressures (ratio of early diastolic mitral flow velocity to early diastolic mitral annular velocity, r = 0.51, p = 0.003). In multivariate analysis, transmural index and early diastolic mitral flow velocity/early diastolic mitral annular velocity were independent predictors of BNP levels (p <0.05, power of 0.99 at alpha = 0.05). In conclusion, among patients with recent myocardial infarction, high BNP levels are independently associated with extent of myocardial scar tissue and estimated LV filling pressures.

Decreased number of circulating plasmacytoid dendritic cells in patients with atherosclerotic coronary artery disease.

BACKGROUND: Dendritic cells are potent antigen-presenting and immune modulating cells that have been implicated in the development of atherosclerosis. In human blood, two distinct lineages are distinguished: plasmacytoid dendritic cells and myeloid dendritic cells. Although dendritic cells have been described in atherosclerotic plaques, no information exists concerning circulating blood dendritic cells in atherosclerosis. This study aims to evaluate the number of circulating dendritic cells in patients with coronary artery disease. The relation with the extent of coronary artery disease, the clinical syndrome and with a marker of inflammation will be documented. METHODS: Patients with angiographically proven coronary artery disease (n=18) and age and sex-matched controls (n=18) were included. Myeloid dendritic cells and plasmacytoid dendritic cells were detected with the specific blood dendritic cell antigens, blood dendritic cell antigen-1 and blood dendritic cell antigen-2, respectively. RESULTS: Absolute and relative numbers of circulating plasmacytoid dendritic cells were significantly lower in patients with coronary artery disease (5722+/-601/ml and 0.08+/-0.01%) than in controls (12,640+/-1289/ml and 0.21+/-0.02%). Plasmacytoid dendritic cells were more decreased in patients with troponin-positive unstable coronary syndromes than in patients with low troponin values, and tended to be lower in more extensive coronary artery disease. Absolute myeloid dendritic cells numbers tended to be reduced in patients, whereas relative numbers were significantly decreased: 11,857+/-1895/ml versus 15,226+/-928/ml and 0.17+/-0.03% versus 0.26+/-0.01% in controls. CONCLUSIONS: The present study shows a significant decrease of circulating blood dendritic cell antigen-2 positive plasmacytoid dendritic cells in patients with coronary artery disease. The decrease tended to be more pronounced in unstable coronary syndromes and extensive coronary artery disease, suggesting a possible role of dendritic cells in plaque progression and rupture.

Validation of transcatheter aortic valve implantation risk scores in relation to early and mid-term survival: a single-centre study.

OBJECTIVES: The aim of this study was to validate recently proposed risk scores for the prediction of mortality up to 1 year after transcatheter aortic valve implantation (TAVI), using a self-expandable valve (CoreValve). METHODS: In this single-centre study, 225 consecutive patients with severe symptomatic aortic valve stenosis, who underwent TAVI between December 2007 and January 2015, were included. Conventional surgical risk scores (logistic EuroSCORE, EuroSCORE II and STS score) were calculated as well as newly proposed TAVI risk scores (TAVI2-SCORe, STT Score and OBSERVANT score). Medium-term survival of the patients was assessed up to 1 year after TAVI. RESULTS: The median age was 82 (77-86) years and 45.3% were male. Patients were categorized into 'non-high risk' or 'high risk' according to logistic EuroSCORE >20%, EuroSCORE II >8%, STS score >10%, TAVI2-SCORe >2, STT score >12% and OBSERVANT score >6. Thirty-day and 1-year survival rates were significantly different between 'non-high-risk' and 'high-risk' patients according to the STS score (1 year: low: 84.4% vs high: 67.0%, P = 0.010) and according to OBSERVANT score (1 year: low: 85.2% vs high: 68.4%, P = 0.005). In contrast, TAVI2-SCORe and STT score did not discriminate 'non-high-risk' and 'high-risk' patients. This was confirmed by Cox regression analysis [STS score >10%: hazard ratio: 2.484 (1.206-5.115), P = 0.014; OBSERVANT score >6: hazard ratio: 2.532 (1.295-4.952), P = 0.007]. CONCLUSIONS: In this single-centre study, OBSERVANT and STS score most accurately predicted early and mid-term survival in patients undergoing TAVI, using a self-expandable valve (CoreValve).

Red cell distribution width improves the prediction of prognosis after transcatheter aortic valve implantation.

OBJECTIVES: The aim of this study was to determine if red cell distribution width (RDW) could improve the prediction of prognosis after transcatheter aortic valve implantation (TAVI). METHODS: In this single-centre study, 197 consecutive patients underwent TAVI (median age 82 (77-86), 46.2% men). Normal RDW at baseline was defined as ≤15.5%, elevated RDW at baseline was defined as >15.5%. Ouctomes according to the Valve Academic Research Consortium 2 and survival up to one year were compared between these groups. RESULTS: Compared with the patients with RDW ≤15.5% (n = 168), those with RDW >15.5% (n = 29) had a higher Society of Thoracic Surgeon (STS) score (7.2 vs 5.0%, P = 0.041), higher systolic pulmonary arterial pressure (50 vs 41 mmHg, P = 0.021) and lower haemoglobin (11.5 vs 12.4 mg/dl, P = 0.003). Patients with RDW >15.5% developed significantly more adverse events after TAVI (major vascular complications: 10.3 vs 1.8%, P = 0.042; aortic regurgitation grade II-IV: 50.0 vs 18.0%, P = 0.001) and survival up to 1 year was significantly lower (85.6 vs 65.2%, log-rank: P = 0.007). In addition, RDW >15.5% at baseline was the most significant predictor for mortality (hazard ratio: 2.701 (1.279-5.704), P = 0.009), even when the STS score was added to the model [RDW >15.5%: hazard ratio: 2.276 (1.045-4.954), P = 0.038]. CONCLUSIONS: Elevated RDW is a significant predictor for adverse events and increased 1-year mortality after TAVI. Adding RDW to the classical STS score could be a valuable strategy to improve preoperative risk assessment in potential TAVI candidates.

Effect of short-term treatment with pravastatin on cytokines and cytokine receptors in patients with chronic heart failure due to ischemic and nonischemic disease.

The antiinflammatory effect of lipoproteins through neutralization of circulating endotoxin has questioned the safety of lipid-lowering drugs in chronic heart failure (CHF). We measured serum levels of interleukin-6, tumor necrosis factor (TNF)-alpha, and soluble TNF-alpha receptors 1 and 2 before and after 1-month treatment with pravastatin 40 mg in 58 patients with CHF. Short-term treatment with pravastatin attenuated the immune response in patients with CHF due to ischemic or nonischemic etiology.

Intracellular monocyte cytokine production and CD 14 expression are up-regulated in severe vs mild chronic heart failure.

BACKGROUND: The role of circulating monocytes in the process of low-grade inflammation, characteristic of chronic heart failure (CHF), has recently been questioned. Lipopolysaccharide (LPS) desensitization has been proposed to mediate reduced monocyte cytokine elaboration in patients with severe CHF. METHODS: Intracellular monocyte production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, and monocyte CD 14 expression were measured flow-cytometrically without and after 8-hour LPS stimulation in 46 patients with CHF and in a healthy control group. RESULTS: Basal cytokine concentrations were similar for the control and the mild CHF groups (New York Heart Association [NYHA] Class I or II). After LPS stimulation, IL-6 (p=0.002) and TNF-alpha levels (p=0.001) were lower in the latter group, whereas IL-1 beta production was comparable. For the moderate-severe CHF patients, unstimulated IL-1 beta (p=0.04) was higher, whereas IL-6 (p=0.2) and TNF-alpha (p=0.1) levels were not different from the controls. Measurement of LPS-stimulated cytokine production showed no differences between the control group and patients with moderate-severe CHF (all p= 0.5). Upon comparing mild vs moderate-severe CHF patients, higher levels of unstimulated cytokine production (IL-1 beta, p=0.002; IL-6, p=0.01; TNF-alpha, p=0.003), stimulated IL-1 beta (p=0.002) and IL-6 (p=0.008) were found in the latter patients. CD 14 expression in the moderate-severe CHF group was higher than in the mild-CHF group (p = 0.03) and was strongly related to stimulated IL-1 beta (r=0.62, p<0.0001), IL-6 (r=0.56, p=0.0002) and TNF-alpha (r=0.41, p=0.006) production. CONCLUSIONS: CD 14 expression and monocyte cytokine production, both unstimulated and after LPS stimulation, are increased in moderate-severe CHF when compared with mild CHF. These data suggest that circulating monocytes, possibly via increased CD 14 expression, may play a significant role in the immunologic dysbalance observed in advanced CHF.

Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis.

OBJECTIVE: Previously, we demonstrated that activated inducible NO synthase (iNOS)-expressing foam cells in human carotid plaques often produce autofluorescent (per)oxidized lipids (ceroid). Here, we investigate whether intraplaque microvessels can provide foam cells with lipids and trigger macrophage activation. METHODS AND RESULTS: Microvessels (von Willebrand factor [vWf] immunoreactivity), activated macrophages (iNOS immunoreactivity), and ceroid were systematically mapped in longitudinal sections of 15 human carotid endarterectomy specimens. An unbiased hierarchical cluster analysis classified vascular regions into 2 categories. One type with normal vWf expression and without inflammatory cells was seen, and another type with cuboidal endothelial cells, perivascular vWf deposits, and iNOS and ceroid-containing foam cells was seen in 4 (27%) of 15 plaques. The perivascular foam cells frequently contained platelets (glycoprotein Ibalpha) and erythrocytes (hemoglobin, iron), pointing to microhemorrhage/thrombosis and subsequent phagocytosis. Similar lipid-containing cells, expressing both ceroid and iNOS, were generated in atherosclerosis-free settings by incubating murine J774 macrophages with platelets or oxidized erythrocytes and also in vivo in organizing thrombi in normocholesterolemic rabbits. CONCLUSIONS: Focal intraplaque microhemorrhages initiate platelet and erythrocyte phagocytosis, leading to iron deposition, macrophage activation, ceroid production, and foam cell formation. Neovascularization, besides supplying plaques with leukocytes and lipoproteins, can thus promote focal plaque expansion when microvessels become thrombotic or rupture prone.

Aortic regurgitation after transcatheter aortic valve implantation (TAVI) - Angiographic, echocardiographic and hemodynamic assessment in relation to one year outcome.

BACKGROUND: Aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) remains a relatively frequent and life-limiting complication. However, the most prognostically discriminative (and therefore preferred) technique of AR evaluation after TAVI is not yet clearly defined. The aim of this study was to compare angiographic, echocardiographic and hemodynamic assessment of AR after TAVI in relation to one year outcome. METHODS AND RESULTS: In this single center prospective cohort study, angiography (AR grading), echocardiography (AR quantification using color Doppler flow mapping) and invasive hemodynamics (AR index) were assessed before and after TAVI. All patients were followed up to at least one year. A total of 111 consecutive (very) high-risk patients with severe, symptomatic aortic valve stenosis underwent TAVI. No concordant relation could be demonstrated between angiographic, echocardiographic and invasive assessment of AR after TAVI. AR index <25 post TAVI was significantly influenced by left ventricular posterior wall thickness (odds ratio: 1.276, p=0.030) and AR index pre TAVI (odds ratio: 0.948, p=0.019). Neither angiographic nor hemodynamic AR assessments were able to discriminate between good or significantly decreased one year survival. In contrast, color Doppler flow mapping of AR after TAVI was highly reproducible, and able to differentiate between good or significantly decreased one year survival (AR grades 0-I: one year survival 87% vs. AR grades II-III-IV: one year survival 68%, p=0.035). CONCLUSION: Echocardiography using color Doppler flow mapping is the preferred technique to assess prognostically relevant AR after TAVI.

Brachiocephalic artery access in transcatheter aortic valve implantation: a valuable alternative: 3-year institutional experience.

OBJECTIVES: With the expanding use of transcatheter aortic valve implantation (TAVI), we have encountered increasing numbers of patients without ideal femoral access. Although many alternatives have been described, vascular access and access-related complications remain a point of concern. We report our series of 20 patients undergoing TAVI via brachiocephalic artery access. METHODS: Between September 2011 and May 2014, we performed 107 consecutive CoreValve bioprosthesis implantations, of which 20 were by the brachiocephalic approach due to unfavourable iliac or femoral anatomy. RESULTS: No vascular or access-related complications were seen. Procedural feasibility, device success and early safety, as defined by the Valve Academic Research Consortium-2 criteria, were good, at 100, 95 and 95%, respectively. No stroke, transient ischaemic attack, acute kidney injury, major vascular or major bleeding complications were observed. At a mean follow-up of 497 days, the 1-year survival rate is 75.0%. Echocardiography at discharge confirmed moderate paravalvular regurgitation in 1 patient and mild paravalvular leakage in 3 patients, and no paravalvular leak more than moderate was seen. Echocardiography at discharge, 6 months and 1 year after TAVI confirmed persistent low mean transvalvular gradients (9, 9 and 10 mmHg, respectively). CONCLUSIONS: TAVI implantation through the brachiocephalic artery is safe and feasible. The distance between the point of access and the aortic valve annulus is short, improving catheter stability and implant site accuracy. We consider it to be a valuable alternative in patients without femoral access.

Usefulness of early rule-in and rule-out biomarker protocols to estimate ischemia-induced myocardial injury in early chest pain presenters.

Protocols to minimize the time between 2 measurements of troponin or a combination with copeptin have been developed to rapidly rule-in or rule-out myocardial injury (MI) in patients with chest pain. These fast track protocols to rule-in and rule-out MI are not sufficiently validated for early chest pain presenters. The "early presenter" model was tested in 107 stable patients after a short period of myocardial ischemia, induced by stenting of a significant coronary artery stenosis. High-sensitivity troponin T (hsTnT), high-sensitivity troponin I (hsTnI), and copeptin were measured at the start and 90, 180, and 360 minutes after stent implantation. MI was defined as a troponin level more than the upper limit of normal (ULN) and an absolute increase of >50% ULN on the 360-minute sample. A single combined measurement of troponin and copeptin 90 minutes after the onset of ischemia has a low diagnostic value. This increases when serial measurements with 90-minute intervals are included. For ruling in MI, the highest positive predictive value (with a 95% confidence interval [CI]) can be obtained when focusing only on the increase in troponin level, with a positive predictive value of 86% (70, 93) and 80% (67, 90) for hsTnT and hsTnI, respectively. For ruling out MI, a combined absence of any troponin more than the ULN and any significant increase in troponin level perform best with a negative predictive value of 75% (55, 89) and 75% (55, 89) for hsTnT and hsTnI, respectively. In conclusion, in early presenters, rapid biomarker protocols underestimate MI. A standard biomarker assessment after 3 hours is required to adequately rule-in or rule-out myonecrosis.