Aims
We investigated whether myeloid-related protein 8/14 complex (MRP8/14) expressed by infiltrating monocytes and granulocytes may represent a mediator and early biomarker of acute coronary ...syndromes (ACS).
Methods and results
Immunohistochemistry of coronary thrombi was done in 41 ACS patients. Subsequently, levels of MRP8/14 were assessed systemically in 75 patients with ACS and culprit lesions, with stable coronary artery disease (CAD), or with normal coronary arteries. In a subset of patients, MRP8/14 was measured systemically and at the site of coronary occlusion. Macrophages and granulocytes, but not platelets stained positive for MRP8/14 in 76% of 41 thrombi patients. In ACS, local MRP8/14 levels 22.0 (16.2-41.5) mg/L were increased when compared with systemic levels 13.4 (8.1-14.7) mg/L, P = 0.03. Systemic levels of MRP8/14 were markedly elevated 15.1 (12.1-21.8) mg/L, P = 0.001 in ACS when compared with stable CAD 4.6 (3.5-7.1) mg/L or normals 4.8 (4.0-6.3) mg/L. Using a cut-off level of 8 mg/L, MRP8/14 but not myoglobin or troponin, identified ACS presenting within 3 h from symptom onset.
Conclusion
In ACS, MRP8/14 is markedly expressed at the site of coronary occlusion by invading phagocytes. The occurrence of elevated MRP8/14 in the systemic circulation prior to markers of myocardial necrosis makes it a prime candidate for the detection of unstable plaques and management of ACS.
Background We reported the first case of successful transapical transcatheter aortic valve implantation in a human subject in 2005 and have now completed a 12-month follow-up on our first 26 ...patients. This is, to date, the longest follow-up of patients undergoing transapical aortic valve implantation. Methods Between October 2005 and January 2007, 26 patients (13 female) underwent transcatheter transapical aortic valve implantation with either 23- or 26-mm Edwards Lifesciences transcatheter bioprostheses. All patients with symptomatic aortic stenosis were declined for conventional aortic valve replacement because of unacceptable operative risks and were not candidates for transfemoral aortic valve implantation because of poor arterial access. Clinical and echocardiographic follow-up was performed before discharge and at 1, 6, and 12 months. Data from the 17 patients who survived over 12 months were used for comparisons of the baseline and follow-up results. Results The mean age was 80 ± 9 years, and the predicted operative mortality was 37% ± 20% by using logistic EuroSCORE and 11% ± 6% by using the Society of Thoracic Surgeons Risk Calculator. Valves were successfully implanted in all patients. Six patients died within 30 days (30-day mortality, 23%), and 3 patients died from noncardiovascular causes after 30 days (late mortality, 12%). Among patients who survived at least 30 days, 12-month survival was 85%. There were no late valve-related complications. New York Heart Association functional class improved significantly. The aortic valve area and mean gradient remained stable at 12 months (1.6 ± 0.3 cm2 and 9.6 ± 4.8 mm Hg, respectively). Conclusion Our 1-year clinical and echocardiographic outcomes suggest that transapical transcatheter aortic valve implantation is a viable alternative to conventional aortic valve replacement in selected high-risk patients.
Acute myocardial infarction (AMI) is associated with inflammation. However, it remains unclear whether it originates from the ruptured plaque or represents a systemic process.
In 42 patients with ...AMI, a balloon-based embolization protection device and aspiration catheter (PercuSurge) were used during acute coronary interventions. Samples from the site of the ruptured plaque were taken under distal balloon occlusion. Systemic samples were taken from the aorta. Sera, plaques, and thrombi were analyzed for inflammatory markers and lipoproteins. Systemic levels of C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) in the aorta amounted to 3.0 mg/L, 5.0 ng/L, and 22.1 mg/L, respectively (interquartile ranges IQRs, 1.1 to 7.4 mg/L, 5.0 to 6.5 ng/L, and 13.9 to 27.0 mg/L, respectively). In blood surrounding ruptured plaques, local levels of IL-6 (8.9 ng/L; IQR, 5.0 to 16.9 ng/L) and SAA (24.3 mg/L; IQR, 16.3 to 44.0 mg/L) were significantly higher, whereas CRP levels (2.5 mg/L; IQR, 0.9 to 7.7 mg/L) were decreased compared with the aorta (all P<0.0001). The coronary levels of IL-6 determined in vivo showed biological activity in vitro. Harvested thrombus contained CD68-positive monocytes expressing IL-6 and showed extracellularly and intracellularly positive staining for SAA, whereas CRP was found exclusively in the cytoplasm of phagocyting white blood cells.
Coronary levels of IL-6 and SAA at the site of plaque rupture were increased relative to the systemic circulation, indicating local production of biologically active inflammatory mediators. In contrast, CRP was locally decreased, at least in part by uptake by the phagocyting cells, suggesting a systemic origin of the protein.
Abstract Introduction We previously reported increased expression of TLR4 on monocytes in thrombi from patients with acute coronary syndromes (ACS). In mice, myeloid related protein (MRP) 8 and ...MRP14, cytoplasmic proteins of neutrophils and monocytes, activate Toll-like receptor (TLR) 4 during sepsis. In human ACS, we investigated now whether the pro-inflammatory action of MRPs occurs through TLR4 in monocytes derived from thrombi. Methods Coronary thrombi and peripheral blood of 27 ACS patients were analyzed. CD14+ monocytes were isolated and incubated with TLR2 ligand PM3SKA, TLR4 ligand lipopolysaccharide (LPS), MRP8, MRP14, or MRP8/14 heterocomplex. Anti-TLR4 antibodies (HTA125) were used to block TLR4 and polymyxin B (PMB) was employed to inhibit endotoxins. Before and after stimulation, the release of TNFα was measured by ELISA and the expression of TLR4 on CD14+ monocytes was determined by flow cytometry. Further, selected pathways of downstream signaling were analyzed. Results MRP8 and MRP8/14 increased release of TNFα in cultures of CD14+ monocytes, more in cells derived from thrombi compared with matched peripheral blood cells ( p < 0.001). LPS, MRP8, and MRP8/14, but much less PM3SKA and MRP14 alone, stimulated TNFα release, which can be inhibited by HTA125. MRP8/14 enhanced TLR4 expression on monocytes from thrombi ( p < 0.001), but not on monocytes from peripheral blood of the same patients. Conclusion In ACS, MRP8 and MRP8/14 complex are specific ligands of TLR4, which induce the release of TNFα and probably other pro-inflammatory agents from monocytes. This specific MRP8/14-dependent pathway with striking similarities to sepsis increasing expression of TLR4 in thrombi appears to be involved in the pathogenesis of coronary occlusion and may represent a novel therapeutic target in ACS.
Surgical aortic valve replacement (AVR) has been associated with systemic inflammatory reactions. Yet, the role of inflammation following transcatheter aortic valve implantation (TAVI) has not been ...fully elucidated.
In a total of 40 patients evaluated by the 'heart team,' this retrospective study assessed levels of high-sensitive C-reactive protein (hs-CRP) and leukocyte counts following 'uneventful' AVR and TAVI. Four groups of matched patients were compared (AVR; transapical and transfemoral Edwards SAPIEN TA ES and TF ES, respectively; and transfemoral Medtronic CoreValve TF CV). A postprocedural increase of both hs-CRP levels and leukocyte counts was observed (P<.001) with peak levels 48 hours after the procedures. Comparing treatment groups, hs-CRP levels at 48 hours were significantly higher following AVR and TA ES compared to TF ES and TF CV (P<.04). Leukocyte counts at 48 hours were higher following TA ES compared to TF ES and TF CV (P<.03). Multivariate analysis incorporating both hs-CRP levels and leukocyte counts confirmed significant differences for all measurements over time (P<.001). Furthermore, the treatment group significantly influenced postprocedural hs-CRP levels and leukocyte counts (P<.001).
Both AVR and TAVI evoke a postprocedural inflammatory response. Higher hs-CRP levels and leukocyte counts following AVR and apical TAVI suggest less inflammation following femoral procedures.
Transcatheter aortic valve implantation (TAVI) has become an accepted treatment option for severe aortic stenosis (AS) in high-risk individuals. Yet, current results are difficult to compare given ...the lack of standardized definitions.
TAVI was performed in 130 high-risk individuals. The Edwards SAPIEN (n = 50) and the Medtronic CoreValve (n = 80) prostheses were implanted by transfemoral (75%) or transapical (25%) access. Outcomes at 30 days and 1 year are reported according to the newly established Valve Academic Research Consortium (VARC) criteria. Median follow-up was 235 days (range, 44-490 days). Thirty-day device success was high (91.5%). Combined safety endpoint at 30 days was 20.8%, with an all-cause mortality of 11.5%. Major vascular complications (11.5%), life-threatening or disabling bleeding (8.5%), and acute kidney injury (6.2%) were further major adverse events. At 1-year follow-up, valve performance was accurate in 94.7% of patients. However, prosthetic-valve associated complications, such as new left bundle branch block (20.0%) or permanent pacemaker implantation (34.7%), were common; cumulative prosthetic-valve associated complications were significantly more frequent in patients treated with a Medtronic CoreValve prosthesis (p = 0.0012). Overall 1-year survival was 80%, with the VARC combined efficacy endpoint (composite of survival, freedom from therapy failure, and accurate valve performance) met in 70.2%. In particular, at 1 year, 68.5% of the patients were living independently at home.
The newly established VARC standardized definitions are useful for TAVI outcome reporting.
Transcatheter aortic valve implantation (TAVI) has become an established therapy for severe aortic stenosis (AS) in high-risk elderly individuals. Concomitant coronary artery disease (CAD) is ...frequently encountered in this patient population and may have an impact on outcomes. Hence, in patients with both severe AS and CAD, a bespoke therapy of both AS and/or CAD appears mandatory.
We report a series of 5 patients with severe AS and concomitant CAD considered for TAVI who underwent fractional flow reserve (FFR) for hemodynamic assessment of coronary lesions.
In 3 patients, a 2-staged procedure was undertaken with FFR measurements at the time of invasive assessment and TAVI thereafter. In the remaining 2 patients, FFR measurements were performed immediately prior to the TAVI procedure with deferral of percutaneous coronary intervention (PCI) in one and ad hoc PCI in the other patient. All 5 patients had uneventful FFR measurements and procedural TAVI outcomes. One patient with a staged approach noted a significant improvement in symptoms already after PCI.
FFR provides an effective and safe strategy to assess hemodynamic significance of coronary lesions in patients with severe AS and concomitant CAD considered for TAVI.
Nebivolol is a newer β1-selective adrenergic receptor antagonist, which unlike classic β-blockers, lowers systemic vascular resistance by direct vasodilator effects possibly involving NO. This study ...was designed to determine the effects of nebivolol on small arteries, which contribute to the most part of systemic vascular resistance. Mesenteric arteries, isolated from 9-week-old Wistar-Kyoto (WKY) rats, were studied under perfused and pressurized conditions using a video dimension analyzer. Aortic rings from the same animals were suspended in organ chambers, and isometric tension was measured. Experiments were performed during contraction to prostaglandin F2α. In small arteries, nebivolol (10 to 3 × 10 M) induced concentration-dependent relaxations (maximum, 55 ± 8%). The relaxations were less pronounced as compared with those to acetylcholine (maximum, 99 ± 2%; p < 0.05), but were significantly greater than those to atenolol (maximum, 2 ± 0%; p < 0.05). Nebivolol-induced responses were markedly reduced by the NO-synthase inhibitor N-nitro-L-arginine methylester (L-NAME; 10 M; maximum, 11 ± 2%; p < 0.05). This inhibition could be entirely reversed by pretreatment with L-arginine (10 M; maximum, 46 ± 7%), a precursor of NO. In contrast to mesenteric arteries, nebivolol did not affect vascular tension of precontracted aortas. These findings indicate that nebivolol induces NO-mediated relaxations in small arteries but not large elastic vessels and therefore, independent of its antihypertensive action, might be effective in protecting the microcirculation in various cardiovascular disease states.
Abstract only
Background.
Transcatheter aortic valve implantation (TAVI) is increasingly recognized as an alternative to surgery for patients with severe, symptomatic aortic stenosis and high or ...prohibitive operative risk. Despite prospective evidence that TAVI can be performed with acceptable 30-day mortality, the potential for vascular, neurologic or cardiac complications exists.
Method.
One hundred and sixty-three balloon-expandable TAVIs were performed between November 2005 and February 2008 at St. Paul’s Hospital, Vancouver, Canada. Valves were implanted using a transarterial (n=110) or transpical approach (n=53). Clinical and echocardiographic data was prospectively collected.
Results.
Overall 30-day mortality rate was 11.0% in this selected high risk population but mortality decreased by 50% in the second half of this cohort. Current systems require a large sheath (22 to 24 Fr) potentially injurious to femoral and iliac arteries. Unplanned percutaneous (n=2) or surgical (n=11) interventions were performed in 14 patients to treat peripheral vascular complications. Temporary endovascular balloon occlusion can provide hemostasis while definitive treatment is implemented. Acute complications associated with apical access include bleeding and tamponade. Intra-procedural deaths occurred in 1.2% of patients due to arterial perforation (n=1) and apical hemorrhage (n=1). Stroke rate was 4.3%. Positioning errors can result in significant paravalvular regurgitation, mitral valve injury (n=1) and valve embolization (n = 7). Paravalvular leak can be reduced by redilation of an under-expanded prosthesis or implantation of a second valve to extend the sealing cuff. Cases of embolization were all satisfactorily managed with re-expansion of the prosthesis distally in the aorta. Coronary ostial obstruction by a bulky leaflet was confirmed in 1 patient. Permanent pacemakers were implanted in 9 patients (5.5%) due to new heart block.
Conclusion.
This early TAVI experience demonstrated the potential for a variety of potential complications. However as experience and knowledge increased over time the rate of adverse events appeared to fall. Careful screening, technological advances and greater experience will allow for safer procedures.
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