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Background— Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDL Healthy ) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDL CAD and HDL Healthy on the activation of endothelial anti- and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes. Methods and Results— HDL was isolated from patients with stable CAD (HDL sCAD ), an acute coronary syndrome (HDL ACS ), and healthy subjects. HDL Healthy induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E–deficient mice in vivo. In contrast, HDL sCAD and HDL ACS did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen-activated protein kinase–mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDL Healthy were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDL sCAD and HDL ACS as mechanisms leading to altered effects on endothelial apoptosis. Conclusions— The present study demonstrates for the first time that HDL CAD does not activate endothelial antiapoptotic pathways, but rather stimulates potential endothelial proapoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease.

ObjectivesThis study was undertaken to compare the hemodynamic performance of a percutaneous bioprosthesis to that of surgically implanted (stented and stentless) bioprostheses for the treatment of severe aortic stenosis.MethodsFifty patients who underwent percutaneous aortic valve implantation (PAVI) with the Cribier-Edwards or Edwards SAPIEN bioprosthetic valve (Edwards Lifesciences, Inc., Irvine, California) were matched 1:1 for sex, aortic annulus diameter, left ventricular ejection fraction, body surface area, and body mass index, with 2 groups of 50 patients who underwent surgical aortic valve replacement (SAVR) with a stented valve (Edwards Perimount Magna [SAVR-ST group]), or a stentless valve (Medtronic Freestyle, Medtronic, Minneapolis, Minnesota [SAVR-SL group]). Doppler echocardiographic data were prospectively obtained before the intervention, at discharge, and at 6- to 12-month follow-up.ResultsMean transprosthetic gradient at discharge was lower (p < 0.001) in the PAVI group (10 ± 4 mm Hg) compared with the SAVR-ST (13 ± 5 mm Hg) and SAVR-SL (14 ± 6 mm Hg) groups. Aortic regurgitation (AR) occurred more frequently in the PAVI group (mild: 42%, moderate: 8%) compared with the SAVR-ST (mild: 10%, moderate: 0%) and SAVR-SL (mild: 12%, moderate: 0%) groups (p < 0.0001). At follow-up, the mean gradient in the PAVI group remained lower (p < 0.001) than that of the SAVR-ST group, but was similar to that of the SAVR-SL group. The incidence of severe prosthesis-patient mismatch was significantly lower (p = 0.007) in the PAVI group (6%) compared with the SAVR-ST (28%) and SAVR-SL (20%) groups. However, the incidence of AR remained higher (p < 0.0001) in the PAVI group compared with the 2 other groups.ConclusionsPAVI provided superior hemodynamic performance compared with the surgical bioprostheses in terms of transprosthetic gradient and prevention of severe prosthesis-patient mismatch, but was associated with a higher incidence of AR.

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 cm 2 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.

Objectives: Early clinical outcomes in selected high-risk patients undergoing catheter-based aortic valve replacement (AVR) compare favorably with conventional surgical AVR. Improved understanding of the mechanisms of success and failure of transcatheter AVR will likely improve outcomes further. To this end, we examined our experience during the developmental phases of transcatheter AVR and describe the causes and management of prosthetic valve malposition. Methods: Transcatheter balloon-expandable AVR was performed in 170 patients at two centers. Malposition was defined as prosthetic valve implantation in a location other than within the native valve. Patients were prospectively identified and followed as part of an ongoing database. Results: Valve malposition occurred in 9 of 170 patients (5.3%). Final position was supravalvular in eight of nine cases. In all cases, embolization to the ascending aorta occurred within a few cardiac cycles following deployment. Importantly, late embolization was not observed. In most cases, the prosthesis was uneventfully repositioned in the more distal aorta. Positioning was subvalvular in one patient (0.6%), resulting in a severe regurgitation with residual native valve stenosis. Implantation of a second transcatheter valve was attempted in six patients and was successful in all. Conventional AVR was performed in two patients, with early mortality in one. At late follow-up (mean 412 days), seven of nine patients remain alive (78%) with a functioning prosthesis and relief of aortic stenosis. Conclusions: Malposition of current balloon-expandable aortic valves is a largely preventable complication. An improved understanding of the procedure will likely minimize this possibility and mitigate the consequences should malposition occur. © 2008 Wiley-Liss, Inc.

Objectives Transcatheter aortic valve replacement (AVR) is a promising approach to aortic valve disease. The implications of this new therapy are not entirely known. We describe the potential for the development of new atrioventricular (AV) block. Background Atrioventricular block is a known complication of conventional surgical AVR. Block is presumed to occur as a consequence of surgical trauma to the cardiac conduction tissue during excision of the diseased aortic valve and debridement of the calcified annulus. Whether AV block might occur as a consequence of nonsurgical implantation of an aortic stent valve is unknown. Methods We reviewed our experience with patients undergoing transcatheter AVR using both the percutaneous transarterial and the open-chest direct left ventricular apical ventriculotomy approaches. Patients were considered at high risk for conventional surgery because of comorbidities. Continuous arrhythmia monitoring was performed for at least 48 h after the valve implantation procedure. Patients who developed apparently new, clinically significant AV block were identified. Results Transcatheter AVR was successfully performed in 123 patients. Seventeen of these patients (13.8%) had pre-existing permanent pacemakers. Two patients (1.6%) required pacemaker implantation because of pre-existing intermittent bradycardia. Seven patients (5.7%) developed new and sustained complete AV block requiring pacemaker implantation. An additional 4 patients (3.3%) developed new and sustained left bundle branch block but did not require pacemaker implantation. Conclusions As with conventional AVR surgery, transcatheter AVR may result in impaired atrioventricular conduction. Physicians and patients should be aware of the potential for AV block and pacemaker dependence.

Background— Percutaneous aortic valve replacement represents an endovascular alternative to conventional open heart surgery without the need for sternotomy, aortotomy, or cardiopulmonary bypass. Methods and Results— Transcatheter implantation of a balloon-expandable stent valve using a femoral arterial approach was attempted in 50 symptomatic patients with severe aortic stenosis in whom there was a consensus that the risks of conventional open heart surgery were very high. Valve implantation was successful in 86% of patients. Intraprocedural mortality was 2%. Discharge home occurred at a median of 5 days (interquartile range, 4 to 13). Mortality at 30 days was 12% in patients in whom the logistic European System for Cardiac Operative Risk Evaluation risk score was 28%. With experience, procedural success increased from 76% in the first 25 patients to 96% in the second 25 ( P =0.10), and 30-day mortality fell from 16% to 8% ( P =0.67). Successful valve replacement was associated with an increase in echocardiographic valve area from 0.6±0.2 to 1.7±0.4 cm 2 . Mild paravalvular regurgitation was common but was well tolerated. After valve insertion, there was a significant improvement in left ventricular ejection fraction ( P P =0.01), and functional class ( P Conclusion— Percutaneous valve replacement may be an alternative to conventional open heart surgery in selected high-risk patients with severe symptomatic aortic stenosis.

Objectives: Gender differences in patients presenting with suspected acute coronary syndromes (ACS) have not yet been fully characterized. The aim of this study was to assess gender-related disparities in clinical profiles, biomarkers and diagnoses of patients with suspected ACS. Methods: This single-centre, prospective cohort study included 377 consecutive patients presenting with suspected ACS to the emergency department. Suspected ACS was defined as a request for conventional troponin T (c-cTnT) measurements on clinical grounds. Results: Women were older than men (p = 0.004), and had a lower prevalence of known coronary artery and peripheral vascular disease (p < 0.05). c-cTnT was positive in 8% of female and in 14% of male patients (p = 0.16), TIMI risk score and cardiac biomarkers including c-cTnT, hs-cTnT, myoglobin, creatine kinase, N-terminal pro-brain natriuretic peptide, myeloid-related protein 8/14 and pregnancy-associated plasma protein A were lower in women (p < 0.05). Women were less frequently diagnosed with ACS (30 vs. 51%), and were not referred for urgent coronary angiography as often as men (p < 0.001). In multivariate analysis, female gender was associated with a lower referral for coronary angiography (HR 0.41, 95% CI 0.23-0.78, p = 0.006). Conclusions: In patients with suspected ACS, women presented with different biomarker profiles, and were less often diagnosed with ACS and referred to coronary angiography.

OBJECTIVES: Aortic valve calcification and changes after transcatheter aortic valve implantation (TAVI) were specifically assessed by computed tomography (CT). The main difference between TAVI and the conventional technique is the compression of the cusps of the calcified native valve against the aortic wall before implantation. The objective of this study was to quantify the segmented calcification in the area of the basal annular plane before and after TAVI. METHODS: The CT scans of 20 patients (13 male and 7 female; mean age: 82.9±8.1 years) were assessed. The aortic valve calcification was segmented; derived from this segmentation volume, mass and Hounsfield units (HU)/density of the calcifications on the annulus and cusps before and after TAVI were evaluated. Pre- and postoperative data were compared regarding potential calcification loss and calcification distances to the left and right coronary ostia. RESULTS: Significantly lower postprocedural mean volumes and masses for all cusps (P< 0.001) were found. The mean differences in the volume for the non-coronary, right-coronary and left-coronary cusp were �156.8 ± 53.73, �155.5 ± 62.54 and �115 ± 57.53 mm 3 , respectively, and differences in mass were �88.78 ± 29.48, �95.2 ± 39.27 and �71.56 ± 35.62 mg, respectively. Over all cusps, mean HU increased after intervention [784.41 ± 92.5 HU (pre) and 818.63 ± 78.71 HU (post); P< 0.004]. In 80.03% of all cusps, calcification loss was found; all patients were affected. Significantly lower (P< 0.047) postprocedural mean distances were found from the left and right coronary ostia to the next calcification point. CONCLUSIONS: Our results show a significant loss of calcification in all patients after TAVI, with a reduction in the calcification distances to the coronary ostia and the compression of calcification in the area of the device landing zone. The clinical implications of this finding need to be investigated further.

Objectives: In the evaluation of patients considered for transcatheter aortic valve implantation (TAVI), the EuroScore II might be superior to established risk scores. Methods: We assessed the performance of the EuroScore II in predicting mortality in a cohort of 350 TAVI patients. Results: The EuroScore II and the logistic EuroScore were higher in nonsurvivors compared to survivors at 30 days (12.6 ± 1.8 vs. 7.5 ± 0.3%, p < 0.001 for EuroScore II, and 27.7 ± 2.8 vs. 22.1 ± 0.8%, p = 0.04 for logistic EuroScore), while the STS-PROM score did not differ (7.3 ± 0.8 vs. 6.4 ± 0.3%, p = 0.09). The area under the curve (AUC) was 0.70 for the EuroScore II, 0.61 for the logistic EuroScore and 0.59 for the STS-PROM score for predicting 30-day mortality. Based on the estimated 30-day mortality risk, 3 risk groups were identified, a low-risk (EuroScore II ≤4%, 30-day mortality 1.2%), an intermediate-risk (EuroScore II between 4% and 9%, 30-day mortality 8.6%) and a high-risk group (EuroScore II >9%, 30-day mortality, 17.1%; p = 0.03). Regarding cumulative mortality, the AUC was 0.67 for the EuroScore II, 0.62 for the logistic EuroScore and 0.55 for the STS-PROM score for predicting mortality at total follow-up. Conclusions: In this patient cohort, the EuroScore II performed best in predicting short- and long-term mortality.

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Mechanical forces and strain induced by tran-scatheter aortic valve implantation are usually named as origins for postoperative left ventricular arrhythmia associated with the technique. No quantitative data has been published so far to substantiate this common belief. As a first step towards quantitative analysis of the biomechanic situation at the aortic root after transapical aortic valve implantation, we present a spline-based method for reconstruction of the implanted stent from CT images and for locally measuring the deformation of the stent.

An 81-year-old woman was referred for NSTEMI complicated by cardiogenic shock. Urgent invasive assessment revealed a subtotal left anterior descending artery (LAD) stenosis, severe aortic stenosis (mean gradient 60 mmHg, aortic valve area 0.5 cm2), decreased left ventricular (LV) function [left ventricular ejection fraction (LVEF) 49%], grade 3+ mitral regurgitation (MR), and severe pulmonary hypertension. In view of her critical situation, acute LAD–percutaneous coronary intervention and aortic valvuloplasty were performed with …

Aims Inflammation plays a key role in acute coronary syndromes (ACS). Toll-like receptors (TLR) on leucocytes mediate inflammation and immune responses. We characterized leucocytes and TLR expression within coronary thrombi and compared cytokine levels from the site of coronary occlusion with aortic blood (AB) in ACS patients. Methods and results In 18 ACS patients, thrombi were collected by aspiration during primary percutaneous coronary intervention. Thrombi and AB from these patients as well as AB from 10 age-matched controls without coronary artery disease were assessed by FACS analysis for cellular distribution and TLR expression. For further discrimination of ACS specificity, seven non-coronary intravascular thrombi and eight thrombi generated in vitro were analysed. In 17 additional patients, cytokine levels were determined in blood samples from the site of coronary occlusion under distal occlusion and compared with AB. In coronary thrombi from ACS, the percentage of monocytes related to the total leucocyte count was greater than in AB (47 vs. 20%, P = 0.0002). In thrombi, TLR-4 and TLR-2 were overexpressed on CD14-labelled monocytes, and TLR-2 was increased on CD66b-labelled granulocytes, in comparison with leucocytes in AB. In contrast, in vitro and non-coronary thrombi exhibited no overexpression of TLR-4. Local blood samples taken under distal occlusion revealed elevated concentrations of chemokines (IL-8, MCP-1, eotaxin, MIP-1α, and IP-10) and cytokines (IL-1ra, IL-6, IL-7, IL-12, IL-17, IFN-α, and granulocyte-macrophage colony-stimulating factor) regulating both innate and adaptive immunity (all P < 0.05). Conclusion In ACS patients, monocytes accumulate within thrombi and specifically overexpress TLR-4. Together with the local expression patterns of chemokines and cytokines, the increase of TLR-4 reflects a concerted activation of this inflammatory pathway at the site of coronary occlusion in ACS.

Background— Transcatheter aortic valve implantation is an alternative to open heart surgery in patients with aortic stenosis. However, long-term data on a programmatic approach to aortic valve implantation remain sparse. Methods and Results— Transcatheter aortic valve implantation was performed in 168 patients (median age, 84 years) in the setting of severe aortic stenosis and high surgical risk. Access was transarterial (n=113) or, in the presence of small iliofemoral artery diameter, transapical (n=55). The overall success rate was 94.1% in this early experience. Intraprocedural mortality was 1.2%. Operative (30-day) mortality was 11.3%, lower in the transarterial group than the transapical group (8.0% versus 18.2%; P =0.07). Overall mortality fell from 14.3% in the initial half to 8.3% in the second half of the experience, from 12.3% to 3.6% ( P =0.16) in transarterial patients and from 25% to 11.1% ( P =0.30) in transapical patients. Functional class improved over the 1-year postprocedure period ( P 3 years and a median of 221 days, structural valve failure was not observed. Conclusions— Transcatheter aortic valve implantation can result in early and sustained functional improvement in high-risk aortic stenosis patients. Late outcome is determined primarily by comorbidities unrelated to aortic valve disease.

CLINICAL SUMMARY An 88-year-old man with symptomatic severe aortic stenosis underwent percutaneous TAVI with a 26-mm SAPIEN valve (Edwards Lifesciences LLC, Irvine, Calif). Comorbid conditions included coronary artery bypass with patent retrosternal grafts, transient ischemic attacks, bilateral carotid endarterectomies, atrial fibrillation, repaired abdominal aneurysm, prostate cancer, and renal failure. Estimated 30day mortality for AVR was 35% by means of logistic EuroSCORE and 11.1% by means of the Society of Thoracic Surgeons National Database Risk Calculator. The procedure was performed without difficulty, but the final valve position was suboptimal, being slightly low (ventricularly), with the ventricular aspect of the stent abutting the anterior leaflet of the mitral valve (MV). Moderate paravalvular aortic regurgitation (AR) was treated with repeated balloon redilation without altering the valve position. Six-month transthoracic echocardiographic analysis showed trivial AR and mitral regurgitation. The patient presented 11 months after implantation with fever and Streptococcus angiosus in blood cultures. Also noted were a dental visit 6 weeks before and lack of compliance with endocarditis prophylaxis. Transesophageal echocardiographic analysis demonstrated mild-to-moderate paravalvular AR, a 13 3 8–mm ruptured anterior mitral leaflet aneurysm contiguous with the aortic prosthesis, and severe mitral regurgitation (Figure 1). Redo sternotomy was performed during cardiopulmonary bypass after cannulating the right axillary artery and right internal jugular vein. The bioprosthesis was well-seated below the coronary arteries with incomplete endothelialization of the uppermost struts and covered with nodular excrescences (Figure 2). It withstood extraction while fully expanded but was removable when grasped with forceps, which were

After cloning and sequencing chicken connective tissue growth factor (cCTGF) we showed that in serum-deprived chicken embryo fibroblasts (CEF) the initial decline of cCTGF mRNA was followed by an increase. Human CTGF that was produced as a soluble protein in Escherichia coli by thioredoxin co-expression inhibited serum-deprivation induced apoptosis of CEF at I(50) of approximately 8pM, demonstrating a function of CTGF at concentrations observed in supernatants of fibroblasts. CTGF was neither mitogenic for CEF nor for other cell types. In conclusion CTGF supports very efficiently survival of certain cells without stimulating their cell growth.

ObjectivesWe describe procedural and clinical outcomes in a high-risk cohort undergoing transcatheter aortic valve replacement with early next-generation transcatheter valve and delivery systems.BackgroundPercutaneous aortic valve replacement is gaining acceptance as a viable option in patients at high surgical risk. Broader application will require further advances in valve and delivery system technology.MethodsTransarterial aortic valve replacement was attempted in 25 patients (mean age 85 years) determined to be at high surgical risk due to comorbidities. A new delivery catheter system (RetroFlex 2, Edwards Lifesciences, Irving, California) was utilized in combination with either a balloon-expandable SAPIEN (Edwards Lifesciences) valve or a next-generation low-profile cobalt-chromium bovine pericardial SAPIEN XT (Edwards Lifesciences) valve.ResultsPercutaneous valve replacement was successful in all 25 high-risk patients. Aortic valve area increased from 0.59 ± 0.15 cm2to 1.60 ± 0.27 cm2. In this high-risk cohort (Society of Thoracic Surgeons and logistic EuroSCORE estimates of surgical mortality were 8.9% and 21.0%, respectively), 30-day mortality was 0%.ConclusionsTechnical and procedural advances in catheter systems and prosthetic valves designed for percutaneous aortic valve delivery may contribute to increased procedural success and improved clinical outcomes.