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The role of platelet glycoprotein IIb/IIIa inhibitor therapy in patients with mild renal impairment is not well characterized. Our objective was to explore the associations of creatinine clearance (CrCl) with outcomes in a trial of eptifibatide therapy in patients who underwent percutaneous coronary intervention (PCI). We analyzed 48-hour and 30-day outcomes of patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. Patients were randomly assigned to placebo or eptifibatide as an adjunct to stent implantation (1,755 with CrCl > or =60 ml/min and 289 with CrCl <60 ml/min). CrCl was calculated using the Cockcroft and Gault formula, and the associations of CrCl with outcomes were evaluated using logistic regression models. Patients with CrCl <60 ml/min were more likely to be older, women, hypertensive, and have a history of coronary artery bypass surgery, stroke, or peripheral vascular disease. The interaction of eptifibatide with CrCl had borderline significance for the 30-day outcome (p = 0.109). Treatment effect trended toward a greater magnitude in patients with lower CrCl (60 ml/min) (odds ratio 0.53, confidence interval 0.34 to 0.83) compared with those with higher CrCl (90 ml/min) (odds ratio 0.68, confidence interval 0.49 to 0.94). An accompanying increase in bleeding risk also was not apparent with lower CrCl. The treatment effect of eptifibatide is realized regardless of renal function and trends toward being greater in patients with mild renal impairment. [ABSTRACT FROM AUTHOR]

Background: Transcatheter edge-to-edge repair (TEER) improved outcomes in patients with heart failure (HF) and severe secondary mitral regurgitation (SMR) compared with guideline-directed medical therapy (GDMT) alone regardless of the severity of baseline left ventricular ejection fraction (LVEF). The study aimed to evaluate the effect of early changes in LVEF after TEER and GDMT alone in patients with HF and severe SMR., Methods: Within the COAPT trial, we evaluated outcomes according to changes in LVEF from baseline to 30 days. The primary outcome was all-cause death or HF hospitalization (HFH) between 30 days and 2 years., Results: Among 432 patients with paired echocardiographic data, 182 (42.1%) had increased LVEF (LVEF change 6.0% ± 4.9%) and 250 (57.9%) had a decrease or no change in LVEF (LVEF change -6.6% ± 5.6%) from baseline to 30 days. LVEF at 30 days increased more frequently with GDMT alone compared with TEER plus GDMT (51.4% vs 33.0%; P = .0001). Between 30 days and 2 years, there were no significant differences in death or HFH in the increase LVEF and the decrease LVEF groups (58.8% vs 51.4%; multivariable-adjusted HR, 0.97; 95% CI, 0.87-1.08; P = .59). TEER plus GDMT reduced the 30-day to 2-year rate of death or HFH compared with GDMT alone consistently in patients with increase LVEF and decrease LVEF (P int = 0.75)., Conclusions: Among patients with HF and severe SMR, early improvements in LVEF were more frequent with GDMT alone compared with TEER plus GDMT but were not associated with subsequent outcomes at 2 years. TEER reduced death or HFH during 2-year follow-up irrespective of early LVEF changes., (© 2024 The Author(s).)

Background: Data from a 5-year follow-up of outcomes after transcatheter edge-to-edge repair of severe mitral regurgitation, as compared with outcomes after maximal doses of guideline-directed medical therapy alone, in patients with heart failure are now available., Methods: We randomly assigned patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy to undergo transcatheter edge-to-edge repair plus receive medical therapy (device group) or to receive medical therapy alone (control group) at 78 sites in the United States and Canada. The primary effectiveness end point was all hospitalizations for heart failure through 2 years of follow-up. The annualized rate of all hospitalizations for heart failure, all-cause mortality, the risk of death or hospitalization for heart failure, and safety, among other outcomes, were assessed through 5 years., Results: Of the 614 patients enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of hospitalization for heart failure through 5 years was 33.1% per year in the device group and 57.2% per year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.41 to 0.68). All-cause mortality through 5 years was 57.3% in the device group and 67.2% in the control group (hazard ratio, 0.72; 95% CI, 0.58 to 0.89). Death or hospitalization for heart failure within 5 years occurred in 73.6% of the patients in the device group and in 91.5% of those in the control group (hazard ratio, 0.53; 95% CI, 0.44 to 0.64). Device-specific safety events within 5 years occurred in 4 of 293 treated patients (1.4%), with all the events occurring within 30 days after the procedure., Conclusions: Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite guideline-directed medical therapy, transcatheter edge-to-edge repair of the mitral valve was safe and led to a lower rate of hospitalization for heart failure and lower all-cause mortality through 5 years of follow-up than medical therapy alone. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079.)., (Copyright © 2023 Massachusetts Medical Society.)

Objectives: We report the 30-day outcomes from the roll-in cohort of the CLASP IID trial, representing the first procedures performed by each site., Background: The currently enrolling CLASP IID/IIF pivotal trial is a multicenter, prospective, randomized trial assessing the safety and effectiveness of the PASCAL transcatheter valve repair system in patients with clinically significant MR. The trial allows for up to three roll-in patients per site., Methods: Eligibility criteria were: DMR ≥3+, prohibitive surgical risk, and deemed suitable for transcatheter repair by the local heart team. Trial oversight included a central screening committee and echocardiographic core laboratory. The primary safety endpoint was a 30-day composite MAE: cardiovascular mortality, stroke, myocardial infarction (MI), new need for renal replacement therapy, severe bleeding, and non-elective mitral valve re-intervention, adjudicated by an independent clinical events committee. Thirty-day echocardiographic, functional, and quality of life outcomes were assessed., Results: A total of 45 roll-in patients with mean age of 83 years and 69% in NYHA class III/IV were treated. Successful implantation was achieved in 100%. The 30-day composite MAE rate was 8.9% including one cardiovascular death (2.2%) due to severe bleeding from a hemorrhagic stroke, one MI, and no need for re-intervention. MR≤1+ was achieved in 73% and ≤2+ in 98% of patients. 89% of patients were in NYHA class I/II (p < .001) with improvements in 6MWD (30 m; p = .054) and KCCQ (17 points; p < .001)., Conclusions: Early results representing sites with first experience with the PASCAL repair system showed favorable 30-day outcomes in patients with DMR≥3+ at prohibitive surgical risk., (© 2021 Wiley Periodicals LLC.)

Objectives: This study sought to assess the sex-specific outcomes in patients with heart failure (HF) with 3+ and 4+ secondary mitral regurgitation (SMR) treated with transcatheter mitral valve repair (TMVr) plus guideline-directed medical therapy (GDMT) versus GDMT alone in the COAPT trial., Background: The impact of sex in patients with HF and severe SMR treated with TMVr with the MitraClip compared with GDMT alone is unknown., Methods: Patients were randomized 1:1 to TMVr versus GDMT alone. Two-year outcomes were examined according to sex., Results: Among 614 patients, 221 (36.0%) were women. Women were younger than men and had fewer comorbidities, but reduced quality of life and functional capacity at baseline. In a joint frailty model accounting for the competing risk of death, the 2-year cumulative incidence of the primary endpoint of all HF hospitalizations (HFH) was higher in men compared with women treated with GDMT alone. However, the relative reduction in HFHs with TMVr was greater in men (HR: 0.43; 95% CI: 0.34-0.54) than women (HR: 0.78; 95% CI: 0.57-1.05) (P interaction  = 0.002). A significant interaction between TMVr versus GDMT alone treatment and time was present for all HFHs in women (HR: 0.57; 95% CI: 0.39-0.84, and HR: 1.39; 95% CI: 0.83-2.33 between 0-1 year and 1-2 years after randomization, respectively, P interaction  = 0.007) but not in men (HR: 0.48; 95% CI: 0.36-0.64, and HR: 0.33; 95% CI: 0.21-0.51; P interaction  = 0.16). Female sex was independently associated with a lower adjusted risk of death at 2 years (HR: 0.64; 95% CI: 0.46-0.90; P = 0.011). TMVr consistently reduced 2-year mortality compared with GDMT alone, irrespective of sex (P interaction  = 0.99)., Conclusions: In the COAPT trial, TMVr with the MitraClip resulted in improved clinical outcomes compared with GDMT alone, irrespective of sex. However, the impact of TMVr in reducing HFH was less pronounced in women compared with men beyond the first year after treatment. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Tria] [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures The COAPT trial was sponsored by Abbott. Dr Kosmidou has received research grant support from Amgen. Dr Lindenfeld has received research grant support from AstraZeneca; and consulting fees from Abbott Vascular, AstraZeneca, CVRx, Edwards Lifesciences, Impulse Dynamics, Boehringer Ingelheim, VoluMetrix, and V-Wave. Dr Abraham has received research grant support and consulting fees from Abbott Vascular. Dr Rinaldi has received advisory-board fees from Boston Scientific; teaching-course fees from Abbott and Edwards Lifesciences; consulting fees from Abbott, Boston Scientific, and Edwards Lifesciences; research support and grants from Boston Scientific; and proctor fees from Abbott and Edwards Lifesciences. Dr Kapadia holds stock options in Navigate Cardiac Structures, Inc. Dr Rajagopal has received consultant fees from Abbott Vascular; has served on the steering committee for TRILUMINATE study (sponsored by Abbott); screening committee for Medtronic Intrepid; and is founder and CEO of Opus Medical Therapies. Dr Sarembock has served on an advisory board and as a consultant for Boston Scientific. Dr Rogers has received research grant support from Abbott, Boston Scientific, and Edwards Lifesciences; and has served as a consultant for Abbott, Baylis, Boston Scientific, and Gore. Dr Mack has served as co-primary investigator for the PARTNER trial for Edwards Lifesciences and COAPT trial for Abbott and has served as study chair for the APOLLO trial for Medtronic. Dr Stone has received speaker fees or other honoraria from Cook, Terumo, and Orchestra Biomed; has served as consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In the COAPT trial, transcatheter mitral valve repair with the MitraClip plus maximally tolerated guideline-directed medical therapy (GDMT) improved clinical outcomes compared with GDMT alone in symptomatic patients with heart failure (HF) and 3+ or 4+ secondary mitral regurgitation (SMR) due to left ventricular (LV) dysfunction., Aims: In this COAPT substudy, we sought to evaluate two-year outcomes in HF patients with reduced LV ejection fraction (HFrEF; LVEF ≤40%) versus preserved LVEF (HFpEF; LVEF >40%) and in those with severe (LVEF ≤30%) versus moderate (LVEF >30%) LV dysfunction., Methods: The principal effectiveness outcome was the two-year rate of death from any cause or HF hospitalisations (HFH). Subgroup analysis with interaction testing was performed according to baseline LVEF; 472 patients (82.1%) had HFrEF (mean LVEF 28.0%±6.2%; range 12% to 40%) and 103 (17.9%) had HFpEF (mean LVEF 46.6%±4.9%; range 41% to 65%), while 292 (50.7%) had severely depressed LVEF (LVEF ≤30%; mean LVEF 23.9%±3.8%) and 283 (49.3%) had moderately depressed LVEF (LVEF >30%; mean LVEF 39.0%±6.8%)., Results: The two-year rate of death or HFH was 56.7% in patients with HFrEF and 53.4% with HFpEF (HR 1.16, 95% CI: 0.86-1.57, p=0.32). MitraClip reduced the two-year rate of death or HFH in patients with HFrEF (HR 0.50, 95% CI: 0.39-0.65) and HFpEF (HR 0.60, 95% CI: 0.35-1.05), pint=0.55. MitraClip was consistently effective in reducing the individual endpoints of mortality and HFH, improving MR severity, quality of life, and six-minute walk distance in patients with HFrEF, HFpEF, LVEF ≤30%, and LVEF >30%., Conclusions: In the COAPT trial, among patients with HF and 3+ or 4+ SMR who remained symptomatic despite maximally tolerated GDMT, the MitraClip was consistently effective in improving survival and health status in patients with severe and moderate LV dysfunction and those with preserved LVEF.

Background: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) resulted in fewer heart failure hospitalizations (HFHs) and lower mortality at 24 months in patients with heart failure (HF) with mitral regurgitation (MR) secondary to left ventricular dysfunction compared with guideline-directed medical therapy (GDMT) alone., Objectives: This study determined if these benefits persisted to 36 months and if control subjects who were allowed to cross over at 24 months derived similar benefit., Methods: This study randomized 614 patients with HF with moderate-to-severe or severe secondary MR, who remained symptomatic despite maximally tolerated GDMT, to TMVr plus GDMT versus GDMT alone. The primary effectiveness endpoint was all HFHs through 24-month follow-up. Patients have now been followed for 36 months., Results: The annualized rates of HFHs per patient-year were 35.5% with TMVr and 68.8% with GDMT alone (hazard ratio [HR]: 0.49; 95% confidence interval [CI]: 0.37 to 0.63; p < 0.001; number needed to treat (NNT) = 3.0; 95% CI: 2.4 to 4.0). Mortality occurred in 42.8% of the device group versus 55.5% of control group (HR: 0.67; 95% CI: 0.52 to 0.85; p = 0.001; NNT = 7.9; 95% CI: 4.6 to 26.1). Patients who underwent TMVr also had sustained 3-year improvements in MR severity, quality-of-life measures, and functional capacity. Among 58 patients assigned to GDMT alone who crossed over and were treated with TMVr, the subsequent composite rate of mortality or HFH was reduced compared with those who continued on GDMT alone (adjusted HR: 0.43; 95% CI: 0.24 to 0.78; p = 0.006)., Conclusions: Among patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite GDMT, TMVr was safe, provided a durable reduction in MR, reduced the rate of HFH, and improved survival, quality of life, and functional capacity compared with GDMT alone through 36 months. Surviving patients who crossed over to device treatment had a prognosis comparable to those originally assigned to transcatheter therapy. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures This study was supported by Abbott. Dr. Mack has received grant support from Abbott. Dr. Lindenfeld has received grant support from AstraZeneca; and has received consulting fees from Abbott, AstraZeneca, CVRx, Edwards Lifesciences, Impulse Dynamics, Boehringer Ingelheim, VoluMetrix, and V-Wave. Dr. Abraham has received personal fees from Abbott; has received consulting fees from Boehringer Ingelheim, Respicardia, Sensible Medical, CVRx, and Impulse Dynamics; and has received salary support from V-Wave Medical, all for work done in the field of heart failure. Dr. Kar has received grants from Abbott, Boston Scientific, Edwards Lifesciences, and 4TECH; has been a consultant for Boston Scientific, Edwards Lifesciences, Medtronic, and 4TECH; and holds stock options in 4TECH. Dr. Lim has received institutional grant support from Abbott. Dr. Grayburn has received grants from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, W.L. Gore, Neochord, and CardioValve; and has received personal fees from Abbott, Edwards Lifesciences, Medtronic, W.L. Gore, and 4C Medical. Dr. Rinaldi has been a consultant and speaker for Abbott, Boston Scientific, and Edwards Lifesciences; has taught courses and has been a proctor for Abbott and Edwards Lifesciences; and has been a member of the advisory board and received a research grant for Boston Scientific. Dr. Sarembock has been a consultant for Boston Scientific. Dr. Rogers has received a research grant and physician training services from and has been a member of the advisory board for Abbott. Dr. Marx has received honorarium for membership in CEC from the Cardiovascular Research Foundation. Dr. Cohen has received institutional research grants and consulting fees from Abbott, Edwards LifeSciences, Medtronic, and Boston Scientific. Dr. Weissman has received grants from Abbott, Boston Scientific, Medtronic, and Edwards Lifesciences. Dr. Stone has been a speaker for and has received honoraria from Cook, Terumo, QOOL Therapeutics, and Orchestra Biomed; has been a consultant for Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, and Cardiomech; and holds equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to examine the relationship between baseline left ventricular (LV) geometry and outcomes after transcatheter aortic valve replacement (TAVR)., Methods: Patients undergoing TAVR (n = 206) had baseline LV geometry classified as (1) concentric hypertrophy, (2) eccentric hypertrophy, (3) concentric remodeling, or (4) normal. Descriptive statistics, Kaplan-Meier time-to-event analysis, and Cox regression were performed., Results: Distribution of baseline LV geometry differed between male and female patients (χ 2  = 16.83, P = .001) but not at 1 month (χ 2  = 2.56, P = .47) or 1 year (χ 2  = 5.68, P = .13). After TAVR, a majority of patients with concentric hypertrophy evolved to concentric remodeling. Survival differed across LV geometry groups at 1 year (χ 2 [3] = 8.108, P = .044, log-rank test) and at 6.5 years (χ 2 [3] = 9.023, P = .029, log-rank test). Compared with patients with concentric hypertrophy, patients with normal geometry (hazard ratio, 2.25; 95% CI, 1.12-4.54; P = .023) and concentric remodeling (hazard ratio, 1.89; 95% CI, 1.12-3.17; P = .016) had higher rates of all-cause mortality., Conclusions: Baseline concentric hypertrophy confers a survival advantage after TAVR. Although baseline patterns of LV geometry appear gender specific (with women demonstrating more concentric hypertrophy), this difference resolves after TAVR., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular filling pressure (LVFP) has been demonstrated to be a major predictor of poor cardiovascular outcomes. However, estimation of LVFP in patients with aortic stenosis is limited by the high prevalence of significant mitral annular calcification. The aim of this study was to investigate the effect of transcatheter aortic valve replacement on LVFP and the relationship of LVFP to mortality and hospitalization., Methods: This was a single-center, retrospective study of 140 consecutive patients in sinus rhythm with significant mitral annular calcification who underwent transcatheter aortic valve replacement for severe aortic stenosis from May 2011 to June 2015. Mean follow-up duration was 3.06 ± 1.48 years (minimum, 2.4 years; maximum, 6.5 years). Diastolic function was assessed using recently proposed criteria for those with significant mitral annular calcification. High LVFP was defined as a mitral E/A ratio > 1.8 or a ratio of 0.8 to 1.8 and isovolumic relaxation time < 80 msec., Results: At baseline, the proportion of patients with high LVFP was 40.7%, similar to 1 month (39.7%) (P = .86). However, the proportion of patients with high LVFP was significantly decreased at 1 year compared with those at baseline (26.9% vs 40.7%, P = .02). Multivariate analysis showed that high LVFP at baseline significantly increased risk for all-cause mortality compared with patients with normal LVFP (hazard ratio, 2.84; 95% confidence interval, 1.33-6.05; P = .007)., Conclusions: High baseline LVFP was associated with a significantly increased all-cause mortality, and LVFP does not improve in the short term but only at 1 year after transcatheter aortic valve replacement., (Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: The thin-strut SYNERGY stent has an abluminal everolimus-eluting bioabsorbable polymer coating designed to facilitate vascular healing and reduce risk of stent thrombosis. In the multicenter, randomized EVOLVE II trial (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]), SYNERGY was noninferior to the durable polymer PROMUS Element Plus everolimus-eluting stent for the primary end point of 1-year target lesion failure. Longer-term clinical follow-up will support the relative efficacy and safety of SYNERGY., Methods: Patients with ≤3 native coronary lesions (reference vessel diameter ≥2.25-≤4.00 mm; length ≤34 mm) in ≤2 major epicardial vessels were randomized 1:1 to SYNERGY (N=838) or PROMUS Element Plus (N=846). EVOLVE II included a Diabetes substudy which pooled patients with diabetes mellitus from the randomized controlled trial (n=263) and from a sequential, single-arm substudy (N=203)., Results: The 5-year target lesion failure rate was 14.3% for SYNERGY and 14.2% for PROMUS Element Plus (P=0.91). Landmark analysis demonstrated similar rates of target lesion failure from discharge to 1-year (P=0.90) and from 1 to 5 years (P=0.94). Definite/probable stent thrombosis was infrequent in both arms (SYNERGY 0.7% versus PROMUS Element Plus 0.9%; P=0.75). There were no significant differences in the rates of cardiac death, myocardial infarction, or revascularization. Among patients with diabetes mellitus, the target lesion failure rate to 1-year was noninferior to a prespecified performance goal and to 5 years was 17.0%., Conclusions: SYNERGY demonstrated comparable outcomes to PROMUS Element Plus, with low rates of stent thrombosis and adverse events through 5 years of follow-up. Five-year clinical outcomes were favorable in patients with diabetes mellitus. These data support the long-term safety and effectiveness of SYNERGY in a broad range of patients., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01665053.

Background: Among patients with heart failure who have mitral regurgitation due to left ventricular dysfunction, the prognosis is poor. Transcatheter mitral-valve repair may improve their clinical outcomes., Methods: At 78 sites in the United States and Canada, we enrolled patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy. Patients were randomly assigned to transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group). The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up. The primary safety end point was freedom from device-related complications at 12 months; the rate for this end point was compared with a prespecified objective performance goal of 88.0%., Results: Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of all hospitalizations for heart failure within 24 months was 35.8% per patient-year in the device group as compared with 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.40 to 0.70; P<0.001). The rate of freedom from device-related complications at 12 months was 96.6% (lower 95% confidence limit, 94.8%; P<0.001 for comparison with the performance goal). Death from any cause within 24 months occurred in 29.1% of the patients in the device group as compared with 46.1% in the control group (hazard ratio, 0.62; 95% CI, 0.46 to 0.82; P<0.001)., Conclusions: Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy, transcatheter mitral-valve repair resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a prespecified safety threshold. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079 .).

Background: Measurement of fractional flow reserve (FFR) to guide coronary revascularization lags despite robust supportive data, partly because of the handling characteristics of traditional coronary pressure wires. An optical pressure-monitoring microcatheter, which can be advanced over a traditional coronary guidewire, facilitates FFR assessment but may underestimate pressure wire-derived FFR., Methods and Results: In this prospective, multicenter trial, 169 patients underwent FFR assessment with a pressure wire alone and with a pressure microcatheter over the pressure wire. An independent core laboratory performed quantitative coronary angiography and evaluated all pressure tracings. The primary end point was the bias or difference between the microcatheter FFR and the pressure wire FFR, as assessed by Bland-Altman analysis. The mean difference between the microcatheter and the pressure wire-derived FFR values was -0.022 (95% confidence interval, -0.029 to -0.015). On multivariable analysis, reference vessel diameter ( P =0.027) and lesion length ( P =0.044) were independent predictors of bias between the 2 FFR measurements. When the microcatheter FFR was added to this model, it was the only independent predictor of bias ( P <0.001). The mean FFR value from the microcatheter was significantly lower than from the pressure wire (0.81 versus 0.83; P <0.001). In 3% of cases (95% confidence interval, 1.3%-6.7%), there was clinically meaningful diagnostic discordance, with the FFR from the pressure wire >0.80 and that from the microcatheter <0.75. These findings were similar when including all 210 patients with site-reported paired FFR data., Conclusions: An optical, pressure-monitoring microcatheter measures lower FFR compared with a pressure wire, but the diagnostic impact appears to be minimal in most cases., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02577484., (© 2017 The Authors.)

Background: Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent., Methods and Results: Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non-ST-segment-elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus-treated subjects, respectively., Conclusions: In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053., (© 2015 American Heart Association, Inc.)

Aims: We sought to determine the feasibility of conducting percutaneous coronary intervention (PCI) in high-risk acute coronary syndrome (ACS) patients utilising the REG1 system consisting of pegnivacogin, an aptameric factor IXa inhibitor, and its controlling agent anivamersen., Methods and Results: In RADAR, ACS patients were randomised to pegnivacogin 1 mg/kg with 25%, 50%, 75%, or 100% anivamersen reversal or unfractionated heparin. Of the 640 patients randomised, 388 (61%) underwent PCI. Major modified ACUITY 30-day bleeding rates were 18% (25% reversal), 12% (50% reversal), 9% (75% reversal), and 7% (100% reversal), compared with 11% with heparin. The corresponding total bleeding rates were 68%, 39%, 35%, 34%, and 38% (heparin). Ischaemic events were less frequent in those receiving pegnivacogin versus heparin (4.4% vs. 7.3%, p=0.3). Thirty-day urgent TVR (1.1% vs. 0.9%, p=1.0), myocardial infarction (4.0% vs. 6.4%, p=0.3), and angiographic complication (11.2% and 10.8%, p=0.9) rates were similar with pegnivacogin and heparin. There were no incidences of clot formation on guidewires or catheters., Conclusions: High-level factor IXa inhibition in ACS patients undergoing PCI, with at least 50% reversal, has a favourable bleeding profile and appears effective at suppressing ischaemic events and thrombotic complications. Larger phase trials in PCI are warranted., Clinical Trials Registration: ClinicalTrials.gov NCT00932100.

In acute coronary syndromes, risk stratification is essential, particularly in patients without ST elevation, and is based upon clinical, electrocardiogram (ECG), and biological markers. Among them, recent and repeated attacks of angina, ST-segment deviation from baseline on the admission ECG as well as elevated markers of myonecrosis (particularly increased troponin levels), myocardial dysfunction (B-type natriuretic peptide [BNP]; N-terminal prohormone of BNP[NT-proBNP]), and inflammation (high-sensitivity C-reactive protein) are predictors of an adverse outcome. These variables can be incorporated into broader risk predictive scores, among which the TIMI (Thrombolysis in Myocardial Infarction) and GRACE (Global Registry of Acute Coronary Events) scores are the most widely used. Two general therapeutic strategies (routine invasive vs conservative or selective invasive) are employed in the treatment of non-ST-segment elevation acute coronary syndrome (NSTEACS). Evidence-based analysis and the current American College of Cardiology/American Heart Association/Society for Cardiac Angiography and Interventions clinical practice guidelines recommend an early invasive treatment strategy (8-24 h) for intermediate or high clinical risk patients with NSTEACS.

Objective: Prediabetic states are associated with accelerated atherosclerosis, but the availability of mouse models to study connections between these diseases has been limited. The aim of this study was to test the selective role of impaired insulin receptor/insulin receptor substrate-1 signaling on atherogenesis., Methods and Results: To address the effects of impaired insulin signaling associated with hyperinsulinemia on atherosclerosis in the absence of obesity and hyperglycemia, we generated insulin receptor (Insr)/insulin receptor substrate-1 (Insr1) double heterozygous apolipoprotein (Apoe)-knockout mice (Insr(+/-)Irs1(+/-)Apoe(-/-)) mice. Insr(+/-)Irs1(+/-)Apoe(-/-) mice fed a Western diet for 15 weeks showed elevated levels of fasting insulin compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. There were no significant differences in glucose, triglyceride, HDL, VLDL, cholesterol levels or free fatty acid in the plasma of Insr(+/-)Irs1(+/-)Apoe(-/-) and Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Atherosclerotic lesions were increased in male (brachiocephalic artery) and female (aortic tree) Insr(+/-)Irs1(+/-)Apoe(-/-) compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Bone marrow transfer experiments demonstrated that nonhematopoietic cells have to be Insr(+/-)Irs1(+/-) to accelerate atherosclerosis. Impaired insulin signaling resulted in decreased levels of vascular phospho-eNOS, attenuated endothelium-dependent vasorelaxation and elevated VCAM-1 expression in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice. In addition, phospho-ERK and vascular smooth muscle cell proliferation were significantly elevated in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice., Conclusions: These results demonstrate that defective insulin signaling is involved in accelerated atherosclerosis in Insr(+/-)Irs1(+/-)Apoe(-/-) mice by promoting vascular dysfunction and inflammation.

High levels of circulating soluble CD40 ligand (sCD40L) are frequently found in patients with hypercholesterolemia, diabetes, ischemic stroke, or acute coronary syndromes, predicting an increased rate of atherosclerotic plaque rupture and restenosis after coronary/carotid interventions. Clinical restenosis is characterized in part by exaggerated neointima formation, but the underlying mechanism remains incompletely understood. This study investigated the role of elevated sCD40L in neointima formation in response to vascular injury in an atherogenic animal model and explored the molecular mechanisms involved. apoE(-/-) mice fed a Western diet developed severe hypercholesterolemia, significant hyperglycemia, and high levels of plasma sCD40L. Neointima formation after carotid denudation injury was exaggerated in the apoE(-/-) mice. In vivo, blocking CD40L with anti-CD40L monoclonal antibody attenuated the early accumulation of Ly-6G(+) neutrophils and Gr-1(+) monocytes (at 3 days) and the late accumulation of Mac-2(+) macrophages (at 28 days) in the denudated arteries; it also reduced the exaggerated neointima formation at 28 days. In vitro, recombinant CD40L stimulated platelet P-selectin and neutrophil Mac-1 expression and platelet-neutrophil co-aggregation and adhesive interaction. These effects were abrogated by anti-CD40L or anti-Mac-1 monoclonal antibody. Moreover, recombinant CD40L stimulated neutrophil oxidative burst and release of matrix metalloproteinase-9 in vitro. We conclude that elevated sCD40L promotes platelet-leukocyte activation and recruitment and neointima formation after arterial injury, potentially through enhancement of platelet P-selectin and leukocyte Mac-1 expression and oxidative activity.

Percutaneous coronary intervention (PCI) has played an integral role in the therapeutic management strategies for patients who present with either acute coronary syndromes or stable angina pectoris. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial enrolled patients with chronic stable angina and at least 1 significant (> or =70%) angiographic coronary stenosis who were randomly assigned to an initial treatment of either PCI in conjunction with optimal medical therapy or optimal medical therapy alone. Although the initial management strategy of PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events, improvement in angina-free status and a reduction in the requirement for subsequent revascularization was observed. An in-depth analysis of the COURAGE trial design and execution is provided.

Objective: Activation of peroxisome proliferator-activated receptors (PPARs) by lipid-lowering fibrates and insulin-sensitizing thiazolidinediones inhibits vascular inflammation, atherosclerosis, and restenosis. Here we investigate if the vasculoprotective and anti-inflammatory enzyme heme oxygenase-1 (HO-1) is regulated by PPAR ligands in vascular cells., Methods and Results: We show that treatment of human vascular endothelial and smooth muscle cells with PPAR ligands leads to expression of HO-1. Analysis of the human HO-1 promoter in transient transfection experiments together with mutational analysis and gel shift assays revealed a direct transcriptional regulation of HO-1 by PPARalpha and PPARgamma via 2 PPAR responsive elements. We demonstrate that a clinically relevant polymorphism within the HO-1 promoter critically influences its transcriptional activation by both PPAR isoforms. Moreover, inhibition of HO-1 enzymatic activity reversed PPAR ligand-mediated inhibition of cell proliferation and expression of cyclooxygenase-2 in vascular smooth muscle cells., Conclusion: We demonstrate that HO-1 expression is transcriptionally regulated by PPARalpha and PPARgamma, indicating a mechanism of anti-inflammatory and antiproliferative action of PPAR ligands via upregulation of HO-1. Identification of HO-1 as a target gene for PPARs provides new strategies for therapy of cardiovascular diseases and a rationale for the use of PPAR ligands in the treatment of other chronic inflammatory diseases.

We hypothesized that myocardial perfusion imaging (MPI) would fail to identify all vascular zones with the potential for myocardial ischemia in patients with multivessel coronary disease (MVD). MPI is based on the concept of relative flow reserve. The ability of these techniques to determine the significance of a particular stenosis in the setting of MVD is questionable. Fractional flow reserve (FFR) can determine the significance of individual stenoses. Thirty-six patients with disease involving 88 arteries underwent angiography, FFR, and MPI. FFR was performed using a pressure wire with hyperemia from intracoronary adenosine. Myocardial perfusion images were analyzed quantitatively and segments assigned to a specific coronary artery. The relation between FFR and perfusion was determined for each vascular zone. Of the 88 vessels, the artery was occluded (n=20) or had an abnormal FFR

Elevated permeability of the endothelium is thought to be crucial in atherogenesis because it allows circulating lipoproteins to access subendothelial monocytes. Both local hemodynamics and cytokines may govern endothelial permeability in atherosclerotic plaque. We recently found that p21-activated kinase (PAK) regulates endothelial permeability. We now report that onset of fluid flow, atherogenic flow profiles, oxidized LDL, and proatherosclerotic cytokines all stimulate PAK phosphorylation and recruitment to cell-cell junctions. Activation of PAK is higher in cells plated on fibronectin (FN) compared to basement membrane proteins in all cases. In vivo, PAK is activated in atherosclerosis-prone regions of arteries and correlates with FN in the subendothelium. Inhibiting PAK in vivo reduces permeability in atherosclerosis-prone regions. Matrix-specific PAK activation therefore mediates elevated vascular permeability in atherogenesis.

Objectives: To demonstrate that fractional flow reserve (FFR) of vessels in patients with high left ventricular mass index (LVMI) should be similar to that of matched vessels in patients with normal LVMI., Background: FFR is a physiologic index of coronary lesion severity. It is not known whether FFR remains useful in the setting of increased LVMI, when microvascular abnormalities may be present., Methods: LVMI was calculated in 84 patients using contrast left ventriculography after validation with cardiac magnetic resonance imaging. Cardiac risk factors, LV ejection fraction (LVEF), minimal lumen diameter (MLD), percent diameter stenosis (%DS), lesion length and FFR were compared in 22 patients with high LVMI to 62 patients with normal LVMI and angiographically-matched vessels., Results: LVMI was 126 +/- 21 g/m2 in the high LVMI group and 84 +/- 21 g/m2 in the normal LVMI group. There were no differences in age, LVEF, diabetes, hypertension or dyslipidemia between groups. Angiographic lesion characteristics were well matched in patients with high versus normal LVMI (MLD 1.3 +/- 0.6 mm vs. 1.3 +/- 0.6 mm, %DS 61 +/- 13% vs. 62 +/- 13%, and lesion length 14.2 +/- 7.0 mm vs. 14.3 +/- 7.0 mm; p = NS for all). Importantly, no difference in FFR was observed (0.79 +/- 0.12 vs. 0.78 +/- 0.16; p = NS) between the groups, and LVMI did not correlate with FFR in a multivariate analysis., Conclusions: FFR of coronary lesions in patients with high LVMI is no different than FFR of angiographically-matched lesions in patients with normal LVMI, suggesting that high LV mass should not limit the utility of FFR as an index of coronary lesion severity.

Objectives: To determine the outcome of consecutive patients with and without acute coronary syndromes (ACS) in whom revascularization was deferred on the basis of fractional flow reserve (FFR)., Background: FFR < 0.75 correlates with ischemia on noninvasive tests and deferral of treatment on the basis of FFR is associated with low event rates in selected populations. Whether these low event rates apply to patients undergoing assessment of moderate stenoses in association with an ACS is not known and is an important clinical question., Methods: Retrospective analysis and 12 month follow-up of consecutive, moderate (50-70%) de novo coronary lesions assessed with FFR., Results: Revascularization was deferred in 120 lesions (111 patients) with FFR > or = 0.75. ACS was present in 35 patients (40 lesions). The clinical, angiographic and coronary hemodynamic characteristics of patients with and without ACS were similar. Among the 35 patients with ACS, there were 3 deaths, 1 MI, and 6 target vessel revascularizations (TVRs) (15% of lesions). Among the 76 patients without ACS, there were 5 deaths, 1 MI, and 7 TVR's (9% of lesions)., Conclusions: Deferral of revascularization based on FFR in patients with ACS and moderate coronary stenoses is associated with acceptable and low event rates at 1 year.

Objective: Periostin is dramatically upregulated in rat carotid arteries after balloon injury. The objective of the present study was to understand mechanisms underlying periostin upregulation in balloon-injured rat carotid arteries and in cultured vascular smooth muscle cells (VSMCs)., Methods and Results: Periostin protein was strongly expressed at 3 days (in the medial SMCs) and 7 days (in the neointima) after injury. It was also abundantly expressed in the neointima in the late phase (at 14 and 28 days) after injury. Periostin upregulation was mediated through PI-3-kinase-dependent signaling pathway. In vivo, wortmannin, a PI-3-kinase inhibitor, inhibited balloon injury-induced Akt phosphorylation and periostin mRNA expression. In vitro, periostin mRNA expression in cultured VSMCs was stimulated by growth factors (transforming growth factor-beta1 (TGF-beta1), fibroblast growth factors (FGFs), PDGF-BB, and angiotensin II). This stimulatory effect was inhibited by the PI-3-kinase inhibitor LY294002. Further, periostin protein was mostly located in the cytoplasma of VSMCs in culture and abundantly secreted into the culture medium (CM) after stimulation with FGF-2, which significantly promoted VSMC migration in vitro. Immunodepletion of periostin from the VSMC-CM or blockade of periostin function with an anti-periostin antibody significantly reduced VSMC migration., Conclusions: Upregulation of periostin expression in rat carotid arteries following balloon injury and in cultured VSMCs after stimulation by growth factors is mediated through PI-3-kinase-dependent signaling pathway. Periostin protein secreted by VSMCs plays a significant role in regulating VSMC migration in vitro.

Objectives: The goal of this study was to determine the proportion of patients with left main coronary disease (LMCD) with unfavorable characteristics for percutaneous coronary intervention (PCI)., Background: Published series suggest that LMCD can be treated percutaneously, however, the proportion of patients in whom PCI is an option based on angiographic criteria is unknown., Methods: In 13,228 consecutive coronary angiograms, 476 (3.6%) patients had < or =60% stenosis of the left main. In 232 patients with unprotected LMCD, the clinical characteristics and angiograms were reviewed with six features chosen as "unfavorable" for PCI: (1) Bifurcation LMCD, (2) occlusion of a major coronary, (3) ejection fraction <30%, (4) occlusion of a dominant RCA, (5) left dominant circulation, and (6) coexisting three-vessel disease. Treatment modality and 1 year mortality were determined., Results: The mean age was 69 years and 68% were male. Unfavorable characteristics were common with at least one unfavorable characteristic seen in 80%. Bifurcation disease was the most common unfavorable characteristic observed (53%) and coexisting three-vessel disease was seen in 38%. Treatment consisted of CABG in 205 (88%), medical therapy in 24 (10%) and PCI in 3 (1%). Among patients referred for CABG, 1 year survival was 88% with similar rates of survival for those with favorable characteristics (86%) compared to those with at least one unfavorable characteristic (88%)., Conclusions: Most patients with LMCD have at least one unfavorable characteristic for PCI suggesting that PCI may be a technically difficult option for most patients with LMCD.

LDL receptor-deficient (LDLR(-/-)) mice exhibit mild hyperlipidemia on a chow diet but develop severe hyperlipidemia on a high fat diet. In this study, we investigated neointimal formation after removal of the endothelium when LDLR(-/-) mice were fed chow or a Western diet containing 42% fat, 0.15% cholesterol, and 19.5% casein. At 10 weeks of age, female mice underwent endothelial denudation of the left common carotid artery. Two weeks after injury, neointimal formation was barely detectable in the injured vessel when mice developed mild hyperlipidemia on the chow diet. In contrast, neointimal lesions were obvious when mice developed severe hyperlipidemia on the Western diet. Immunohistochemical and histological analyses demonstrated the presence of macrophage foam cells and smooth muscle cells in neointimal lesions. The injured artery also exhibited a significant increase in medial area on the Western diet. Plasma levels of MCP-1 and soluble VCAM-1 were significantly elevated by feeding of the Western diet. These data indicate that hyperlipidemia aggravates neointimal growth in LDLR(-/-) mice by promoting foam cell formation and inflammation.

Objectives: We hypothesized that fractional flow reserve (FFR) of an infarct-related artery (IRA) early after myocardial infarction (MI) identifies inducible ischemia on noninvasive imaging., Background: Early after MI, IRAs frequently have angiographically indeterminant lesions. Whether FFR can detect reversible perfusion defects early after MI when dynamic microvascular abnormalities are present is not known., Methods: Rest and dipyridamole (DP)-stress 99mTc sestamibi single-photon emission computed tomography (SPECT) were performed in 48 patients 3.7 +/- 1.3 days after MI, with 23 patients undergoing concurrent myocardial contrast echocardiography (MCE). Angiography, FFR, and percutaneous coronary intervention (PCI) of the IRA (as necessary) were subsequently performed. Follow-up SPECT was performed 11 weeks after PCI to identify true reversibility on baseline SPECT., Results: The sensitivity, specificity, positive and negative predictive value, and concordance of FFR < or =0.75 for detecting reversibility on SPECT were 88%, 50%, 68%, 89%, and 71% (chi-square <0.001), respectively; which improved to 88%, 93%, 88%, 93%, and 91% (chi-square <0.001), respectively, for the detection of true reversibility. The corresponding values of FFR < or =0.75 for detecting reversibility on DP-MCE were 90%, 100%, 100%, 75%, and 93% (chi-square <0.001), respectively, and on either SPECT or MCE were 88%, 93%, 91%, 91%, and 91% (chi-square <0.001), respectively. The optimal FFR value for discriminating inducible ischemia on noninvasive imaging was 0.78., Conclusions: Fractional flow reserve of the IRA accurately identifies reversibility on noninvasive imaging early after MI. These findings support the utility of FFR early after MI.

Atherosclerosis is an inflammatory disease of large arteries. Flow cytometry of aortic cell suspensions showed that B and T lymphocytes and some macrophages and dendritic cells are already present in the adventitia of normal/noninflamed mouse aortas. Adoptively transferred lymphocytes constitutively homed to the aorta and resided within the adventitia up to 7 d after transfer. Lymphocyte trafficking into normal/noninflamed or atherosclerosis-prone aortas was partially L-selectin dependent. Antigen-activated dendritic cells induced increased T lymphocyte proliferation within the aorta 72 h after adoptive transfer. During progression of atherosclerosis in apolipoprotein-E-deficient mice, the total number of macrophages, T cells, and dendritic cells, but not B cells, increased significantly. This alteration in immune cell composition was accompanied by the formation of tertiary lymphoid tissue in the adventitia of atherosclerotic aortas. These results demonstrate that lymphocytes already reside within the normal/noninflamed aorta before the onset atherosclerosis as a consequence of constitutive trafficking. Atherosclerosis induces the recruitment of macrophages and dendritic cells that support antigen presentation.

Care of patients after cardiac catheterization and/or percutaneous coronary intervention is largely the responsibility of nurses. The identification of risk factors for vascular complications from these procedures is important for the development of protocols to prevent complications. This article describes a retrospective, descriptive, and correlational study of 11,119 patients who underwent cardiac catheterization and/or percutaneous intervention, with femoral artery access, in the years 2001 to 2003. Increased risk for vascular complications was found in patients who were older than 70 years, were female, had renal failure, underwent percutaneous intervention, and had a venous sheath.

Lipoma preferred partner (LPP) has been identified as a protein highly expressed in smooth muscle (SM) tissues. The aim of the present study was to determine mechanisms that regulate LPP expression in an in vitro model of SM cell (SMC) differentiation and in stent-induced pig coronary vessel injury. All trans-retinoic acid treatment of A404 cells induced a strong increase in LPP, as well as SM alpha-actin, SM myosin heavy chain, and smoothelin mRNA levels, in a Rho kinase (ROK)-dependent manner. Adenovirus mediated overexpression of myocardin in A404 cells significantly increased LPP mRNA expression. Interestingly, inactivation of RhoA with C3-exoenzyme or treatment with ROK inhibitors strongly inhibited myocardin mRNA expression in retinoic acid-treated A404 cells or human iliac vein SMCs. LPP silencing with short interfering RNA significantly decreased SMC migration. LPP expression was also markedly decreased in focal adhesion kinase (FAK)-null cells known to have impaired migration but rescued with inducible expression of FAK. LPP expression in FAK-null fibroblasts enhanced cell spreading. In stented pig coronary vessels, LPP was expressed in the neointima of cells lacking smoothelin and showed expression patterns identical to those of SM alpha-actin. In conclusion, LPP appears to be a myocardin-, RhoA/ROK-dependent SMC differentiation marker that plays a role in regulating SMC migration.

Hyperlipemia and oxidized LDL (ox-LDL) are important independent cardiovascular risk factors. Ox-LDL has been shown to stimulate vascular smooth muscle cell (VSMC) proliferation. However, the effects of hyperlipemia and the molecular mechanisms mediating hyperlipemia and ox-LDL effects on VSMC growth are poorly understood. The helix-loop-helix (HLH) transcription factor, Id3, is a redox-sensitive gene expressed in VSMC in response to mitogen stimulation and vascular injury. Accordingly, we hypothesize that Id3 is an important mediator of ox-LDL and hyperlipemia-induced VSMC growth. Aortas harvested from hyperlipemic pigs demonstrated significantly more Id3 than normolipemic controls. Primary VSMC were stimulated with ox-LDL, native LDL, sera from hyperlipemic pigs, or normolipemic pigs. VSMC exposed to hyperlipemic sera demonstrated increased Id3 expression, VSMC growth and S-phase entry and decreased p21cip1 expression and transcription. Cells stimulated with ox-LDL demonstrated similar findings of increased growth and Id3 expression and decreased p21cip1 expression. Moreover, the effects of ox-LDL on growth were abolished in cells devoid of the Id3 gene. Results provide evidence that the HLH factor Id3 mediates the mitogenic effect of hyperlipemic sera and ox-LDL in VSMC via inhibition of p21cip1 expression, subsequently increasing DNA synthesis and proliferation.

P-selectin expression has been reported in platelets, endothelial cells, and vascular smooth muscle cells in response to vascular injury. Here, we report P-selectin expression on macrophages in the arterial wall after carotid denudation injury and spontaneous atherosclerosis in atherosclerosis-prone apoE-deficient (apoE(-/-)) mice. Double-immunofluorescence staining revealed robust P-selectin expression in macrophage-rich regions of both denudation-induced carotid neointimal lesions and innominate atherosclerotic plaques. Co-localization of P-selectin with macrophages was verified at the single cell level using double immunostaining plus 4,6-diamidino-2-phenylindole (for nuclei) counterstaining. No platelet staining was seen in association with the macrophage staining, excluding platelet contamination. Furthermore, P-selectin mRNA expression was readily detectable in macrophage-rich plaques of atherosclerotic innominate arteries and blood monocyte-derived macrophages from apoE(-/-) mice. Strong P-selectin expression was also seen in the areas of regenerated endothelium after arterial injury. In addition, co-localization of P-selectin with vascular smooth muscle cells was readily observed in denudation-injured carotid arteries at 7 and 14 days. We conclude that macrophages in carotid injury-induced neointimal lesions and spontaneous atherosclerotic plaques of the innominate artery acquire the ability to express P-selectin, as does regenerating endothelium. These findings provide a potential new paradigm in macrophage-mediated vascular inflammation, atherosclerosis, and neointimal hyperplasia after arterial injury.

Objectives: The objective of this study was to confirm that the efficacy and safety of percutaneous coronary intervention (PCI) in diabetic patients are not compromised by a bivalirudin-based antithrombotic strategy., Background: Previous studies have shown a survival benefit with use of platelet glycoprotein (GP) IIb/IIIa inhibitors in diabetic patients undergoing PCI. The Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial showed the non-inferiority of a strategy of bivalirudin with provisional GP IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. The relative efficacy of these two strategies in diabetic patients has not been studied., Methods: We evaluated the diabetic patients enrolled in the REPLACE-2 trial to assess the impact of these antithrombotic strategies on the short- and long-term outcome after PCI., Results: The REPLACE-2 trial enrolled 1,624 diabetic patients and 4,368 non-diabetic patients. Compared with non-diabetic patients, diabetic patients had similar short-term outcome but higher mortality at 1 year (3.06% vs. 1.85%, p = 0.004). There was no difference in short-term or long-term ischemic events among the diabetic patients randomized to the two arms. Specifically, the 1-year mortality rate was non-significantly lower in the bivalirudin arm, suggesting no differential survival impact of the two strategies (2.3% vs. 3.9%). There was less minor bleeding in the bivalirudin arm in diabetic patients (12.6% vs. 24.4%, p < 0.001), whereas no difference was seen in the incidence of major bleeding (3.0% vs. 3.3%, p = 0.69)., Conclusions: Compared with routine GP IIb/IIIa inhibition, the use of bivalirudin with provisional GP IIb/IIIa inhibitors in diabetic patients is associated with no differences in clinical outcomes at 30 days, a trend toward lesser mortality at 1 year, and a reduction in minor bleeding.

Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-kappaB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin alpha2beta1 on collagen prevents flow-induced NF-kappaB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.

Objectives: The purpose of this study was to compare the cost of percutaneous coronary intervention (PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with that of heparin + routine GP IIb/IIIa inhibition., Background: Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad range of patients undergoing PCI, many patients currently do not receive such therapy because of concerns about bleeding complications or cost. Recently, bivalirudin with provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin + routine GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this novel strategy is unknown., Methods: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to receive bivalirudin with provisional GP IIb/IIIa (n = 2,319) versus heparin + routine GP IIb/IIIa (n = 2,332). Resource utilization data were collected prospectively through 30-day follow-up on all U.S. patients. Medical care costs were estimated using standard methods including bottom-up accounting (for procedural costs), the Medicare fee schedule (for physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based approaches for the remaining hospitalizations., Results: Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic outcomes including death or myocardial infarction were similar for the bivalirudin and GP IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p = 0.002) and minor bleeding (15.1% vs. 28.1%, p < 0.001). Compared with routine GP IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI] $37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p < 0.001 for both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants themselves, hospital savings were due primarily to reductions in major bleeding (cost savings = $107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient)., Conclusions: Compared with heparin + routine GP IIb/IIIa inhibition, bivalirudin + provisional GP IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to $400/patient depending on the analytic perspective.

C57BL/6 (B6) and C3H/HeJ (C3H) are two commonly used mouse strains that differ markedly in atherosclerosis susceptibility. In this study, we determined plaque formation after removal of the endothelium in the two strains carrying the mutant apolipoprotein E gene (apoE(-/-)). At 10 weeks of age, male B6.apoE(-/-) and C3H.apoE(-/-) mice underwent endothelial denudation of the left common carotid artery. Two weeks after injury, B6.apoE(-/-) mice developed significantly larger neointimal lesions in the vessel than their C3H.apoE(-/-) counterparts, although they had comparable plasma cholesterol levels on a chow diet. Feeding of a Western diet aggravated lesion formation in both strains, but the increase was more dramatic in B6.apoE(-/-) mice than in C3H.apoE(-/-) mice. Immunohistochemical and histological analyses demonstrated the presence of macrophage foam cells in neointimal lesions. We then compared neointimal growth in F1 mice reconstituted with bone marrow from B6.apoE(-/-) and C3H.apoE(-/-) mice. No significant lesions were observed 2 weeks after endothelial denudation in the mice reconstituted with bone marrow from either donor. Thus, these data indicate that foam cell formation contributes to neointimal growth in the hyperlipidemic apoE(-/-) model and that neither endothelial cells nor blood cells alone explain the dramatic difference between B6 and C3H mice in plaque formation.

Understanding the mechanisms that regulate cell cycle progression in vascular smooth muscle cells (VSMCs) is key to understanding and modulating vascular lesion formation. Results of the present study provide the first evidence that phosphorylation of the helix-loop-helix factor Id3 in VSMCs occurs in vitro and in vivo and provides a regulatory switch controlling Id3-induced regulation of p21Cip1 and VSMC growth.

Context: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI)., Objective: To determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 year., Design, Setting, and Participants: Follow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002., Interventions: Patients were randomly assigned to receive intravenously bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI., Main Outcome Measures: Incidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollment., Results: At 6 months, death occurred in 1.4% of patients in the heparin plus Gp IIb/IIIa group and in 1.0% of patients in the bivalirudin group (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.43-1.14; P =.15). Myocardial infarction occurred in 7.4% and 8.2% of patients, respectively (HR, 1.12; 95% CI, 0.93-1.34; P =.24), and repeat revascularization was required in 11.4% and 12.1% of patients, respectively (HR, 1.06; 95% CI, 0.91-1.23; P =.45). By 1 year, death occurred in 2.46% of patients treated with heparin plus Gp IIb/IIIa blockade and in 1.89% of patients treated with bivalirudin (HR, 0.78; 95% CI, 0.55-1.11; P =.16). Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patients., Conclusion: Long-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI.

Objective: Mice deficient in apolipoprotein-E (apoE-/-) experience severe hypercholesterolemia that is exacerbated by a high-fat Western-type diet and atherosclerotic lesions spontaneously develop. In addition, we have reported that deficiency of P-selectin dramatically protects against neointimal lesion formation after arterial injury in apoE-/- mice. To define the mechanism, bone marrow transplantation (BMT) after lethal irradiation was used to generate apoE-/- chimeric mice deficient in platelet, but not endothelial, P-selectin., Methods and Results: Mice underwent vascular injury and were euthanized 4 weeks later. Absence of platelet P-selectin (pPS) expression in apoE-/- mice after BMT was confirmed by flow cytometry and Western blot analysis. Lack of pPS in apoE-/- mice resulted in a 62% reduction in neointimal area (45 000+/-27 000 versus 17 000+/-13 000 microm2, P<0.000001) and a 30% reduction (P<0.02) in macrophage infiltration, compared with control apoE-/- BMT. Absence of pPS was also associated with a reduction in plaque neovascularization as compared with pPS-competent controls (0/8 versus 3/8, P<0.05)., Conclusions: Lack of pPS significantly attenuates macrophage recruitment and neointimal lesion formation, indicating that pPS on platelets lining the vessel wall plays a critical role in inflammation after wire-withdrawal injury of the carotid artery in apoE-/- mice.

Background: Diabetic nephropathy is associated with increased cardiovascular events. Coronary atherosclerosis is responsible for many of these events, but other mechanisms such as impaired flow reserve may be involved. The purpose of this study was to define the prevalence and mechanism of abnormal coronary velocity reserve (CVR) in patients with diabetes mellitus who have nephropathy and a normal coronary artery., Methods: Patients undergoing catheterization for clinical purposes were enrolled. CVR was measured with a Doppler ultrasound scanning wire in a normal coronary in 32 patients without diabetes mellitus, 11 patients with diabetes mellitus who did not have renal failure, and 21 patients with diabetes mellitus who had nephropathy. A CVR <2.0 was considered to be abnormal., Results: Patients with diabetes mellitus who had renal failure had a higher incidence of hypertension and left ventricular hypertrophy. The average peak velocity (APV) at baseline was higher in patients with diabetes mellitus who had renal failure. At peak hyperemia, APV increased in all 3 groups, with no difference between groups. The mean CVR for patients without diabetes was 2.8 +/- 0.8 and was not different from that in patients with diabetes mellitus who did not have renal failure (2.7 +/- 0.7), but was lower than that in patients with diabetes mellitus who had renal failure (1.6 +/- 0.5; P < 0.001). Abnormal CVR was observed in 9% of patients without diabetes mellitus, 18% of patients with diabetes mellitus who did not have renal failure, and 57% of patients with diabetes mellitus who had renal failure, and abnormal CVR was caused by an elevation of baseline APV in 66% of these cases. The baseline heart rate and the presence of diabetes mellitus with renal failure were independent predictors of abnormal CVR by multivariable analysis., Conclusions: Patients with diabetic nephropathy have abnormalities in CVR in the absence of angiographically evident coronary disease.

To assess the efficacy of the direct thrombin inhibitor bivalirudin relative to heparin during contemporary coronary intervention, 1,056 patients who underwent elective or urgent revascularization were randomized in a large-scale pilot study to receive heparin (70 U/kg initial bolus) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). All patients received aspirin; pretreatment with clopidogrel was encouraged, and glycoprotein (GP) IIb/IIIa blockade was at the physician's discretion. Stents were placed in 85% of patients; 72% received a GP IIb/IIIa inhibitor, and 56% were pretreated with clopidogrel. Activated clotting times were higher among patients randomized to bivalirudin than among those given heparin before device activation (median 359 vs 293 seconds, p <0.001). The composite efficacy end point of death, myocardial infarction, or repeat revascularization before hospital discharge or within 48 hours occurred in 5.6% and 6.9% of patients in the bivalirudin and heparin groups, respectively (p = 0.40). Major bleeding occurred in 2.1% versus 2.7% of patients randomized to bivalirudin or heparin, respectively (p = 0.52). This trial represents the largest prospective dataset of bivalirudin administered concomitantly with planned GP IIb/IIIa blockade and provides evidence of the safety and efficacy of this combined antithrombotic approach.

Background: The alpha(4)beta(1) integrin (VLA-4) supports rolling and firm adhesion of leukocytes to inflamed tissues via ligation of VCAM-1 or fibronectin expressed on the activated endothelium. We tested the hypothesis that VLA-4 mediates leukocyte recruitment and neointimal growth after arterial injury in the atherosclerosis-prone apolipoprotein E (ApoE)-deficient mouse., Methods: ApoE (-/-) mice fed a Western diet underwent air desiccation injury, and the expression patterns of VLA-4 and VCAM-1 were determined by immunohistochemistry (IHC). To determine the effect of targeted VLA-4 blockade on leukocyte recruitment and neointimal growth, ApoE (-/-) mice received an intraperitoneal injection of a VLA-4 neutralizing monoclonal antibody (PS/2) at the time of injury alone or over a prolonged administration course. Additional mice received an isotype control antibody., Results: IHC demonstrated a marked increase in VLA-4 expression 7 days following injury. Prolonged administration of PS/2 resulted in a 72% reduction (p < 0.02) in neointimal growth 28 days following injury. IHC revealed a marked 95% reduction in neutrophil recruitment at 7 days and a 48% reduction in macrophage recruitment 28 days following injury with prolonged PS/2 administration., Conclusions: Prolonged VLA-4 blockade reduces leukocyte recruitment and neointimal growth following air desiccation injury in ApoE (-/-) mice. These findings demonstrate an important role for VLA-4 in the response to arterial injury., (Copyright 2004 S. Karger AG, Basel)

Fractional flow reserve (FFR) has been shown to be a useful physiologic index of coronary lesion severity in myocardial beds of patients without prior infarction and in those with remote infarction. Acute myocardial infarction (AMI) causes myocardial necrosis and microvascular stunning, embolization, and damage. Whether FFR remains a useful index of epicardial flow in the setting of recent myocardial infarction is not established. Cardiac risk factors, serum troponin I, angiographic minimal lumen diameter (MLD), percent diameter stenosis (DS), lesion length, vessel reference diameter, hyperemic central aortic pressure, hyperemic pressure distal to stenosis, and FFR were compared in 43 vessels subtending recent AMI beds to 25 control vessels, matched by lesion length and MLD, in patients without AMI. There were no differences in DS, MLD, lesion length, or reference diameter between AMI and non-AMI groups. Patients with AMI had mean troponin I levels of 91.8 +/- 162 ng/ml. Left ventricular ejection fraction was significantly lower in patients with than without AMI (55 +/- 9% vs 62 +/- 8%, p <0.05). There were no significant differences in hyperemic central aortic pressure (92 +/- 13 vs 99 +/- 15 mm Hg, p = NS), hyperemic pressure distal to the stenosis (62 +/- 17 vs 66 +/- 19 mm Hg, p = NS), or FFR (0.67 +/- 17 vs 0.68 +/- 17, p = NS) between recent AMI and non-AMI control patients. There was a significant correlation between DS and FFR for both patients with (p <0.001) and without (p = 0.003) infarctions. Thus, FFR and the relation between FFR and DS of lesions subtending AMI was not significantly different from FFR of angiographically matched lesions in patients without AMI.

Few randomized studies compare outcomes for focal vs. diffuse in-stent restenosis (ISR) using conventional treatments. The purpose of this study was to compare the rates of major adverse cardiac events (MACEs) for focal vs. diffuse ISR using conventional techniques. One hundred thirteen patients with ISR were prospectively classified as focal (< 10 mm) or diffuse (> 10 mm). Focal ISR was randomized to balloon angioplasty (n = 29) or restenting (n = 29) and diffuse ISR randomized to rotational atherectomy (n = 30) or restenting (n = 25). At 9 months, patients with focal ISR had higher survival free of MACEs than patients with diffuse ISR (86% vs. 63%; P < 0.005), with no difference between techniques. Only the presence of diffuse ISR was an independent predictor of MACE at 9 months. Thus, focal ISR has a low rate of MACE compared to diffuse ISR, which carries a high event rate regardless of treatment employed., (Copyright 2004 Wiley-Liss, Inc.)

Stents have become the technique of choice for percutaneous revascularization, but in-stent restenosis has remained a clinical challenge. This brief article summarizes the incidence, patterns, and proposed mechanisms of restenosis and outlines its contemporary management with specific focus on the diabetic patient. It includes a synopsis of the strategy of drug-eluting stents, which is the most recent and major advance in percutaneous coronary intervention.