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A concept of "all or nothing" inspired the innovation of a one-pill-once-daily HIV treatment. Atripla® was the one pill that combined efavirenz, emtricitabine, and tenofovir disoproxil fumarate to become the first daily single tablet regimen that forever simplified HIV treatment to enhance patient compliance and thus, sustained viral suppression. The making of Atripla incorporated dry granulation and bilayer compression technologies to achieve stability and bioequivalence in an optimal pill size. In 2011, there lacked a standard of care for chronic hepatitis C infections that was safe, simple, short, free of interferon and ribavirin, and with high cure rates. A fixed-dose combination of ledipasvir and sofosbuvir was developed and approved in 2014 to be the first complete daily single tablet regimen for CHC genotype 1 infection. A spray-drying process for particle morphology engineering in a polymer matrix was used for improving bioavailability.

Attachment styles hold important downstream consequences for mental health through their contribution to the emergence of self-criticism. To date, no work has extended our understanding of the influence of attachment styles on self-criticism at a neurobiological level. Herein we investigate the relationship between self-reported attachment styles and neural markers of self-criticism using fMRI. A correlation network analysis revealed lingual gyrus activation during self-criticism, a marker of visual mental imagery, correlated with amygdala activity (threat response). It also identified that secure attachment positively correlated with lingual gyrus activation, whilst avoidant attachment was negatively correlated with lingual gyrus activation. Further, at greater levels of amygdala response, more securely attached individuals showed greater lingual gyrus activation, and more avoidantly attached individuals showed less lingual gyrus activation. Our data provide the first evidence that attachment mechanisms may modulate threat responses and mental imagery when engaging in self-criticism, which have important clinical and broader social implications.

When a fingerprint is located at a crime scene, a human examiner is counted upon to manually compare this print to those stored in a database. Several experiments have now shown that these professional analysts are highly accurate, but not infallible, much like other fields that involve high-stakes decision-making. One method to offset mistakes in these safety-critical domains is to distribute these important decisions to groups of raters who independently assess the same information. This redundancy in the system allows it to continue operating effectively even in the face of rare and random errors. Here, we extend this "wisdom of crowds" approach to fingerprint analysis by comparing the performance of individuals to crowds of professional analysts. We replicate the previous findings that individual experts greatly outperform individual novices, particularly in their false-positive rate, but they do make mistakes. When we pool the decisions of small groups of experts by selecting the decision of the majority, however, their false-positive rate decreases by up to 8% and their false-negative rate decreases by up to 12%. Pooling the decisions of novices results in a similar drop in false negatives, but increases their false-positive rate by up to 11%. Aggregating people's judgements by selecting the majority decision performs better than selecting the decision of the most confident or the most experienced rater. Our results show that combining independent judgements from small groups of fingerprint analysts can improve their performance and prevent these mistakes from entering courts.

One of the major dilemmas facing physicians is what diagnostic and therapeutic approaches should be recommended to those stable coronary artery disease patients whose symptoms are adequately controlled on medical therapy. This study sought to assess the evidence-based data relating to whether: 1) all patients with significant coronary lesions (i.e., ischemia-producing) should undergo percutaneous coronary intervention (PCI); 2) the best therapeutic approach is optimal medical therapy; or 3) PCI should be performed, but only in certain subsets of patients. We reviewed all recent meta-analyses of prospective randomized trials that compared the outcomes of medical therapy and PCI in stable, symptomatically controlled, coronary artery disease patients. To provide greater insights to the clinician, we then analyzed, in depth, 3 comprehensive and widely quoted randomized trials. Review of recently published (2012) meta-analyses, and the detailed analyses of 3 widely quoted individual studies, indicate no difference exists between PCI and medical therapy in nonfatal MI or in all-cause or cardiovascular mortality. Thus, clinical equipoise exists: in other words, there is no evidence-based justification for adopting 1 therapeutic strategy over the other. Therefore, it is not inappropriate, until additional evidence emerges, for the responsible, experienced physician to weigh several sources of information in formulating a recommendation to the patient, even though definitive evidence-based data are not as yet available. Such sources may include assessment of the individual patient's clinical presentation, assessment of the severity of ischemia, and the patient's precise coronary anatomy. Critical for more-reliable decision making will be future development of accurate measures of the individual patient's risk of MI and/or death, whether by biomarker, imaging, or ischemia assessments., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The optimal percutaneous treatment of drug-eluting stent (DES) in-stent restenosis (ISR) and the correlates for recurrent DES ISR remain unclear., Methods and Results: From 2003 to 2008, 563 patients presenting with recurrent symptoms of ischemia and angiographic ISR after DES implantation were included. Of these, 327 were treated with re-DES (58.1%), 132 underwent vascular brachytherapy (23.4%), and 104 were treated with conventional balloon angioplasty (18.5%). Variables associated with target lesion revascularization at 1 year were explored by individual proportional hazard models. This population presents a high prevalence of comorbidities, including diabetes (43.7%), previous myocardial infarction (MI) (45.8%), coronary bypass graft surgery (39.2%), chronic renal failure (18.8%), and heart failure (17.3%). Baseline clinical characteristics were balanced among the 3 groups; however, patients undergoing vascular brachytherapy presented with more complex lesions and a higher prevalence of prior stent/vascular brachytherapy failure than did the rest of the population. The overall incidence of recurrent DES failure at 1-year follow-up was 12.2%, which was similar among the 3 groups (P=0.41). The rate of the composite end point (death, Q-wave-MI and target lesion revascularization) at 1-year follow-up was 14.1% for re-DES, 17.5% for vascular brachytherapy, and 18.0% for conventional balloon angioplasty (P=0.57). After univariable analysis tested the traditional known covariates related to ISR, none of them were associated with repeat target lesion revascularization., Conclusions: Recurrence of ISR after DES treatment failure is neither infrequent nor benign, and optimal therapy remains unclear and challenging. Given the absence of traditional risk factors for ISR in this population, further research is required to elucidate both the correlates involved in DES ISR and the optimal treatment for this condition.

Background: Original descriptions of the takotsubo syndrome (TS) included a characteristic left ventricular (LV) contraction pattern, "apical ballooning." Recently, several reports have associated contraction patterns not strictly conforming to the original description with TS. The specifics of the contraction pattern seem to set TS apart from the much larger population of patients with acute coronary syndrome (ACS) but no obstructive coronary artery disease (OCAD). This study was undertaken to compare patients with midventricular and apical dysfunction with those with other LV contraction patterns., Hypothesis: If TS can present with a variety of patterns of LV dysfunction, then both those with and those without the pattern should have the clinical components previously assigned to the syndrome., Methods: We studied LV contraction patterns in consecutive ACS patients referred for consideration of emergent or urgent percutaneous coronary intervention., Results: Of the 893 patients evaluated in 2008, we excluded 862 on the basis of OCAD, preexisting LV dysfunction, or an obvious alternative cause of symptoms. The remaining 31 (3.5%) also had no OCAD but manifested an LV contraction abnormality. We compared the 15 patients (1.7%) whose ventriculograms met criteria for TS with the 16 patients (1.8%) whose did not. The most common alternative pattern was global hypokinesis, followed by a variety of segmental contraction abnormalities. Patients with the TS pattern were older and had evidence of greater myocardial injury. More than 85% were women., Conclusions: The TS pattern identifies a distinct subset of ACS patients with a remarkable predominance of postmenopausal women and is therefore fundamental to the definition of this entity. This distinctive facet of the syndrome is likely to be an important clue to its pathogenesis. We did not encounter patients with other patterns of LV dysfunction that could be thought to represent stress-induced cardiomyopathy. Copyright © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose., (© 2011 Wiley Periodicals, Inc.)

Objectives: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD)., Background: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers., Methods: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports., Results: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups., Conclusions: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to determine the success, complications, and survival of patients after balloon aortic valvuloplasty (BAV)., Background: The introduction of transcatheter aortic valve implantation (TAVI) BAV has led to a revival in the treatment of patients with severe aortic stenosis., Methods: A cohort of 262 patients with severe aortic stenosis underwent 301 BAV procedures. Of these, 39 (14.8%) patients had ≥2 BAV procedures. Clinical, hemodynamic, and follow-up mortality data were collected., Results: The cohort mean age was 81.7 ± 9.8 years, and the mean Society of Thoracic Surgeons and logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 13.3 ± 6.7 and 45.6 ± 21.6, respectively. BAV was performed as a bridge to TAVI or to surgical aortic valve replacement in 28 patients (10.6%) and for symptom relief in 234 (89.4%). The mean aortic valve area (AVA) increased from 0.58 ± 0.3 cm(2) to 0.96 ± 0.3 cm(2) (p < 0.001). Of these, 111 (45.0%) had final AVA >1 cm(2), and in 195 patients (79%), AVA increased by >40%. De novo BAV resulted in a higher mean increase in AVA 0.41 ± 0.24 cm(2) versus 0.28 ± 0.24 cm(2) in redo BAV (p = 0.003). Serious adverse events occurred in 47 patients (15.6%), intraprocedural death in 5 (1.6%), stroke in 6 (1.99%), coronary occlusion in 2 (0.66%), severe aortic regurgitation in 4 (1.3%), resuscitation/cardioversion in 5 (1.6%), tamponade in 1 (0.33%), and permanent pacemaker in 3 (0.99%). A vascular complication occurred in 21 patients (6.9%); 34 (11.3%) had a post-procedure rise in creatinine >50%; and 3 (0.99%) required hemodialysis. During median follow-up of 181 days, the mortality rate was 50% (n = 131). The mortality rate in the group with final AVA >1 cm(2) was significantly lower than in the group with final AVA of <1 cm(2) (36.4% vs. 57.9%, p < 0.001). Final AVA was associated with lower mortality (hazard ratio: 0.46, p = 0.03). BAV as a bridge to TAVI or surgical aortic valve replacement had a better outcome compared with BAV alone: mortality rate 7 (25%) versus 124 (52.9%), respectively (p < 0.0001)., Conclusions: Long-term survival is poor after BAV alone. BAV as a bridge to percutaneous or surgical aortic valve replacement is feasible, safe, and associated with better outcome than BAV alone., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: It has been suggested that black race predicts stent thrombosis (ST) after drug-eluting stent implantation. Whether socioeconomic status or comorbid conditions confound the contribution of black race to the development of ST is unclear., Methods and Results: We compared 1594 black patients who underwent drug-eluting stent implantation with 5642 nonblack patients. Overall, 108 definite STs were reported. Multivariable Cox regression analysis was performed with adjustment for comorbidities, including median household income as a marker of socioeconomic status, to assess the impact that black race may have on the development of ST. On univariable analysis, black patients were younger (63.43±12.42 versus 65.15±12.59 years; P<0.001) and more likely to have a history of hypertension (89.8% versus 81.7%; P<0.001), diabetes mellitus (45.5% versus 30.8%; P<0.001), chronic renal insufficiency (19.2% versus 10.7%; P<0.001), and congestive heart failure (18.7% versus 13.1%; P<0.001). Clopidogrel compliance at the time of the ST event was higher in the black than in the nonblack population (87.5% versus 77.8%; P=0.068). After multivariable analysis, including adjustment for median income and clopidogrel compliance, black race emerged as a strong predictor of definite late ST., Conclusions: Black race is an independent predictor of definite drug-eluting stent ST. Because clopidogrel compliance was higher in black patients and socioeconomic status was not associated with ST, further investigation into the potential mechanisms of this influence of race on ST must be pursued.

Background: Transcatheter aortic valve implantation is currently being evaluated in patients with severe aortic stenosis who are considered high-risk surgical candidates. This study aimed to detect incidences, causes, and correlates of mortality in patients ineligible to participate in transcatheter aortic valve implantation studies., Methods and Results: From April 2007 to July 2009, a cohort of 362 patients with severe aortic stenosis were screened and did not meet the inclusion/exclusion criteria necessary to participate in a transcatheter aortic valve implantation trial. These patients were classified into 2 groups: group 1 (medical): 274 (75.7%): 97 (35.4%) treated medically and 177 (64.6%) treated with balloon aortic valvuloplasty; and group 2 (surgical): 88 (24.3%). The medical/balloon aortic valvuloplasty group had significantly higher clinical risk compared with the surgical group, with significantly higher Society of Thoracic Surgeons score (12.8±7.0 versus 8.5±5.1; P<0.001) and logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (42.4±22.8 versus 24.4±18.1; P<0.001). The medical/balloon aortic valvuloplasty group had a higher New York Heart Association functional class, incidence of renal failure, and lower ejection fraction. During median follow-up of 377.5 days, mortality in the medical/balloon aortic valvuloplasty group was 102 (37.2%), and during median follow-up of 386 days, mortality in the surgical group was 19 (21.5%). Multivariable adjustment analysis identified renal failure (hazard ratio [HR]: 5.60), New York Heart Association class IV (HR: 5.88), and aortic systolic pressure (HR: 0.99) as independent correlates for mortality in the medical group, whereas renal failure (HR: 7.45), Society of Thoracic Surgeons score (STS; HR: 1.09) and logistic EuroSCORE (HR: 1.45) were correlates of mortality in the in the surgical group., Conclusions: Patients with severe symptomatic aortic stenosis not included in transcatheter aortic valve implantation trials do poorly and have extremely high mortality rates, especially in nonsurgical groups, and loss of quality of life in surgical groups.

Objectives: We sought to examine the effect of insurance type upon the likelihood of receiving a drug-eluting stent (DES)., Background: Recent guidelines suggest that consideration of a patient's resources should play a role in decisions to use DES. Previous studies have also documented disparities in both access to care and cardiovascular outcomes according to race, insurance, and socioeconomic status. The effect of insurance status upon the decision to use DES is unclear., Methods: Patients undergoing percutaneous coronary intervention (PCI) with stenting from April 2003 to June 2009, the so-called DES era, were retrospectively analyzed. Multivariable logistic regression was performed separately for patients <65 years and patients > or =65 years, with receipt of > or =1 DES during PCI as the outcome variable of interest. Insurance type was categorized as private, Medicare, Medicaid, and uninsured, based upon the primary insurance at discharge. Data regarding duration of clopidogrel therapy at 1 month, 6 months, and 1 year was also collected., Results: Among the 12,584 patients who underwent PCI with stenting, 6,157 (48.9%) had private insurance, 5,689 (45.2%) had Medicare, 467 (3.7%) had Medicaid, and 271 (2.2%) were uninsured at the time of hospital discharge. There were no significant differences by insurance type in duration of dual antiplatelet therapy at 1 year. Both multivariable logistic regressions showed that Medicaid patients (odds ratio [OR]: 0.60; 95% confidence interval [CI]: 0.46 to 0.78 for age <65 years; OR: 0.45; 95% CI: 0.24 to 0.85 for age > or =65 years) and patients without insurance (OR: 0.57; 95% CI: 0.42 to 0.78 for age <65 years; OR: 0.20; 95% CI: 0.05 to 0.86 for age > or =65 years) were less likely to receive DES., Conclusions: Insurance status has a significant impact upon the decision to use DES. Efforts to address this disparity should focus on the patient-provider level., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to determine whether serial autologous infusions of selective high-density lipoprotein (HDL) delipidated plasma are feasible and well tolerated in patients with acute coronary syndrome (ACS)., Background: Low HDL is associated with increased risk of cardiovascular disease. Plasma selective delipidation converts alphaHDL to prebeta-like HDL, the most effective form of HDL for lipid removal from arterial plaques., Methods: ACS patients undergoing cardiac catheterization with >or=1 nonobstructive native coronary artery atheroma were randomized to either 7 weekly HDL selective delipidated or control plasma apheresis/reinfusions. Patients underwent intravascular ultrasound (IVUS) evaluation of the target vessel during the catheterization for ACS and up to 14 days following the final apheresis/reinfusion session. 2-D gel electrophoresis of delipidated plasmas established successful conversion of alphaHDL to prebeta-like HDL. The trial was complete with 28 patients randomized., Results: All reinfusion sessions were tolerated well by all patients. The levels of prebeta-like HDL and alphaHDL in the delipidated plasma converted from 5.6% to 79.1% and 92.8% to 20.9%, respectively. The IVUS data demonstrated a numeric trend toward regression in the total atheroma volume of -12.18 +/- 36.75 mm(3) in the delipidated group versus an increase of total atheroma volume of 2.80 +/- 21.25 mm(3) in the control group (p = 0.268)., Conclusions: In ACS patients, serial autologous infusions of selective HDL delipidated plasma are clinically feasible and well tolerated. This therapy may offer a novel adjunct treatment for patients presenting with ACS. Further study will be needed to determine its ability to reduce clinical cardiovascular events., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: We investigated the incidence, predictors, and prognostic impact of a decline in platelet count (DPC) in patients treated by percutaneous coronary intervention (PCI)., Methods and Results: A total of 10 146 consecutive patients treated by PCI from 2003 to 2006 were included. According to the magnitude of the DPC, the population was divided into four groups: no DPC (<10%), minor DPC (10-24%), moderate DPC (25-49%), and severe DPC (>or=50%). The primary haemorrhagic endpoint was a composite of post-procedure surgical repair major bleeding. The primary ischaemic endpoint was 30-day all-cause mortality-non-fatal myocardial infarction. Among the total population, 36% had a DPC <10%, 47.7% had a DPC of 10-24%, 14% had a DPC of 25-49%, and 2.3% had a DPC >or=50%. On multivariate analysis, moderate and severe DPC were independent predictive factors of the ischaemic outcome. Two procedural practices were identified that, if modified, might reduce the incidence of acquired thrombocytopaenia. Both the intraprocedural use of heparin (as opposed to bivalirudin) and of low molecular weight contrast material were independently associated with severe acquired thrombocytopaenia., Conclusion: Moderate and severe DPC are independent predictors of adverse bleeding and ischaemic outcomes in PCI. Adoption of intraprocedural anticoagulant other than heparin and avoidance of a low molecular weight contrast agent could potentially decrease the occurrence of severe acquired thrombocytopaenia.

Background: Recent data suggest a clinical benefit with the systematic use of thrombus aspiration (TA) for the treatment of ST-elevation myocardial infarction (STEMI). Nevertheless, the impact of TA as a treatment strategy for stent thrombosis (ST) is unknown. This study aimed to analyze the impact of TA use for the treatment of ST on patient outcomes., Methods: From 2003 to 2008, 91 consecutive patients who presented with a definite ST were included in this analysis. We compared procedural success rates and the incidence of the composite criteria death-recurrent MI-recurrent ST at 30 days in patients who were treated with TA (TA group, n = 36) versus those who were not (No-TA group, n = 55)., Results: Baseline characteristics were similar between the two groups except for the body mass index: 26.2 +/- 5.4 vs. 29.3 +/- 6.2 in the TA and No- TA groups, respectively (p = 0.028). ST presented more likely as STEMI in the TA group: 86.1% vs. 67.3% (p = 0.043). Except for TA use, there was no difference in the treatment therapeutics between groups, including for glycoprotein IIb/IIIa inhibitors. The rate of procedural success was higher in the TA group than in the No-TA group: 88.9% vs. 70.9% (p = 0.043). The incidence of the endpoint of death-recurrent MI-recurrent ST was significantly lower in the TA group: 22.2% vs. 47.2% (p = 0.026). By multivariate analysis, TA use was independently associated with a decrease in the composite criteria (HR = 0.45, p = 0.039)., Conclusion: This study suggests that TA use for ST treatment permits an improvement in patient outcomes at 30 days with a significant decrease in the incidence of the composite criteria death-recurrent MI-recurrent ST. Further prospective studies are needed, however, to definitively address the benefit of TA use in this particular setting.

Objectives: We used serial intravascular ultrasound (IVUS) to assess disease progression in nonintervened saphenous vein graft (SVG) segments to determine the natural rate of disease progression in SVG., Background: There are no serial IVUS studies of disease progression or luminal compromise in SVGs., Methods: We assessed serial (baseline and follow-up at 16.2 +/- 7.4 months) IVUS findings in 50 nonintervened SVG segments in 44 patients. The SVG age was 13.5 +/- 3.6 years., Results: Overall, from baseline to follow-up, plaque area increased (Delta = +0.58 +/- 1.25 mm(2), p = 0.003), and SVG and minimum lumen area (MLA) decreased (Delta = -0.50 +/- 1.14 mm(2), p = 0.002, and Delta = -1.08 +/- 1.28 mm(2), p < 0.001, respectively). The MLA decreased in 34 lesions (Delta = -1.67 +/- 1.08 mm(2)), and MLA increased in 16 lesions (Delta = +0.19 +/- 0.47 mm(2)). Compared with lesions with an increase in MLA, lesions with a decrease in MLA were associated with: 1) larger baseline SVG and plaque areas and plaque burden (15.57 +/- 3.90 mm(2) vs. 11.55 +/- 2.30 mm(2), p < 0.001; 7.97 +/- 3.77 mm(2) vs. 4.27 +/- 1.92 mm(2), p < 0.001; and 48.7 +/- 14.2% vs. 36.0 +/- 13.4%, p = 0.004, respectively); and 2) a greater decrease in SVG area (Delta = -0.96 +/- 1.05 mm(2) vs. +0.48 +/- 0.58 mm(2), p < 0.001) and greater increase in plaque area (Delta = +0.71 +/- 1.47 mm(2) vs. +0.29 +/- 0.45 mm(2), p < 0.001). The DeltaMLA correlated with both Deltaplaque area (r = -0.589, p < 0.001) and DeltaSVG area (r = 0.470, p = 0.001), and Deltaplaque area correlated with DeltaSVG area (r = 0.436, p = 0.002). There were linear relations between both the Deltaplaque area (r = 0.519, p < 0.001) and Deltalumen area (r = -0.500, p < 0.001) versus follow-up low-density lipoprotein (LDL) cholesterol; a follow-up LDL cholesterol of 100 mg/dl predicted no plaque increase., Conclusions: Lumen loss in nonintervened SVG segments correlated with an increase in plaque area and a decrease in SVG area (plaque growth and negative remodeling) with a linear relationship between plaque growth versus follow-up LDL cholesterol leading to long-term lumen loss.

Objectives: We used virtual histology-intravascular ultrasound (VH-IVUS) to study the relationship between pre-percutaneous coronary intervention (PCI) coronary plaque characteristics and post-PCI cardiac troponin I (cTnI) elevation., Background: Percutaneous coronary intervention is often complicated by post-procedural myocardial necrosis as manifested by elevated cardiac markers., Methods: Eighty consecutive patients (29 stable and 51 unstable angina) with normal pre-PCI cTnI levels were imaged before PCI using VH-IVUS. Patients were divided into 2 groups according to the presence (Group I, n = 38) or absence (Group II, n = 42) of post-PCI cTnI elevation > or =3x the upper limit of normal (0.08 ng/ml)., Results: The absolute and percent necrotic core volumes were significantly greater in Group I than in Group II (13.6 +/- 6.4 mm(3) vs. 7.9 +/- 4.4 mm(3), p < 0.001, and 19.8 +/- 10.4% vs. 12.8 +/- 8.4%, p = 0.015, respectively). The absolute and percent necrotic core areas were significantly greater in Group I than in Group II at the minimum lumen site (1.70 +/- 0.91 mm(2) vs. 0.61 +/- 0.39 mm(2), p < 0.001, and 22.9 +/- 11.7% vs. 10.4 +/- 6.6%, p < 0.001, respectively) and at the largest necrotic core site (2.00 +/- 0.86 mm(2) vs. 0.81 +/- 0.78 mm(2), p < 0.001, and 24.0 +/- 11.7% vs. 12.9 +/- 6.6%, p < 0.001, respectively). The DeltacTnI correlated with: 1) absolute and percent necrotic core area at the minimum lumen site and at the largest necrotic core site; 2) absolute necrotic core volume; 3) percent fibrofatty area at the minimum lumen site; and 4) lesion site plaque burden. In the multivariate analysis, absolute necrotic core area at the minimum lumen site was the only independent predictor of post-PCI cTnI elevation > or =3x the upper limit of normal (odds ratio: 1.318; 95% confidence interval: 1.090 to 1.594, p = 0.004)., Conclusions: The VH-IVUS analysis shows that post-PCI cTnI elevation occurs in lesions with a large necrotic core area. The VH-IVUS may play an important role in detecting which lesions are high risks for myocardial necrosis after PCI.

Background: In-stent restenosis remains the major limitation of percutaneous coronary intervention (PCI), particularly after bare-metal stent (BMS) implantation. Drug-eluting stents (DES) decrease in-stent restenosis, which is thought to have minimal clinical consequences, but may increase the risk of stent thrombosis and its attendant high mortality rate., Aims: To assess the clinical consequences of in-stent restenosis, including severity of associated illness and acute and 1-year outcomes and to compare DES and BMS in-stent restenosis., Methods: Using our prospective PCI registry, we compared data from 1958 consecutive patients hospitalized with BMS in-stent restenosis between January 2000 and April 2003 and all 190 patients with DES in-stent restenosis admitted between April 2003 and September 2006. Risk-adjusted outcomes were calculated using propensity-score matching., Results: An unstable presentation was noted in 78.1% of 2148 patients. Patients with DES in-stent restenosis presented more often with acute myocardial infarction (4.3% versus 1.6%, p<0.001). At 1 year, mortality for all patients was 5.7% and target-vessel revascularization was 21.5%. After risk adjustment, target-vessel revascularization and target-vessel revascularization-major adverse cardiac events were greater in patients with DES in-stent restenosis (respectively, 27.8% versus 19.7%, p=0.05; 32.5% versus 24.3%, p=0.06)., Conclusion: In-stent restenosis is associated with unstable presentation and a higher 1-year adverse events rate than expected in patients undergoing elective PCI. For an identical level of cardiac risk, it seems that DES in-stent restenosis outcomes are slightly worse than BMS in-stent restenosis outcomes.

Objectives: We evaluated the clinical significance of attenuated plaque (hypoechoic plaque with deep ultrasound attenuation)., Background: Attenuated plaques are unusual intravascular ultrasound (IVUS) findings in patients with acute coronary syndrome (ACS)., Methods: We reviewed clinical presentations and angiographic and pre-intervention IVUS findings in 293 ACS patients undergoing percutaneous coronary intervention (PCI) without a distal protection device: 187 with non-ST-segment elevation myocardial infarction (NSTEMI) and 106 with ST-segment elevation myocardial infarction (STEMI)., Results: Attenuated plaque was observed in 75 patients (25.6%): 39.6% of STEMI versus 17.6% of NSTEMI (p < 0.001). (We also reviewed 100 randomly selected patients with stable angina and pre-intervention IVUS; none had attenuated plaque.) Overall, in ACS patients with attenuated plaques: 1) the level of C-reactive protein was higher; 2) angiographic thrombus and initial coronary flow Thrombolysis In Myocardial Infarction flow grade <2 were more common; and 3) IVUS lesion site plaque burden and remodeling index were significantly greater, lesion site luminal dimensions significantly smaller, and thrombus, positive remodeling, and plaque rupture were more common. No-reflow (26.7% vs. 4.6%, p < 0.001) and deteriorated post-PCI coronary blood flow (8.0% vs. 2.8%, p = 0.001) were higher. In ACS patients with normal coronary blood flow at baseline, deterioration in the coronary blood flow post-PCI was more common in lesions with attenuated plaque., Conclusions: Attenuated plaque was more common in ACS patients with STEMI than NSTEMI. Attenuated plaque in ACS patients was associated with a higher C-reactive protein level, more severe and complex lesion morphology, reduced coronary blood flow before PCI, and especially no-reflow after PCI.

The long-term outcome of a moderately diseased left main coronary artery (LMCA) remains unknown. One hundred and fourteen patients who underwent angiographic and intravascular ultrasound (IVUS) evaluation for moderate LMCA disease (< 50% diameter stenosis) without intervention were followed for 5 years. There were 11 patients who underwent coronary artery bypass graft surgery (CABG) within 30 days of IVUS analysis based on IVUS findings and 3 patients who died of noncardiac diseases during the follow-up period. These 14 patients were excluded from the cohort, and 100 patients comprised the study group. Six patients (6%) died (1 of cardiac causes and 5 of unknown causes) at a follow up of 31.5 +/- 17.0 months post-IVUS assessment. Two patients (2%) underwent CABG at a follow up of 19.0 +/- 7.1 months. There were no percutaneous LMCA interventions and no myocardial infarctions. Univariate predictors for events were age, mean plaque and media (P&M) area and plaque burden over the entire length of the LMCA lesion, and minimum luminal area (MLA), P&M area, plaque burden, and arc of calcium > 90 degrees at the MLA site. By multiple logistic regression analysis, plaque burden at the MLA (odds ratio = 1.34, 95% confidence interval 1.04-1.73; p = 0.025) was the only independent predictor of events. In conclusion, moderately diseased LMCAs had a 5- year event rate of 8%. The occurrence of future events in moderate diseased LMCAs is dependent on the amount of disease at the MLA site.

Aims: To assess the impact on clinical outcomes of intravascular ultrasound (IVUS) guidance during drug-eluting stent (DES) implantation. IVUS guidance during percutaneous coronary intervention (PCI) has been demonstrated to be useful in optimizing stent deployment. However, it is not proved that routine use of IVUS guidance with DES implantation can prevent stent thrombosis or restenosis., Methods and Results: The clinical outcomes of 884 patients undergoing IVUS-guided intracoronary DES implantation from April 2003 to May 2006 were compared with the outcomes of a propensity-score matched population undergoing DES implantation with angiographic guidance alone. The primary endpoint of the study was definite stent thrombosis at 12 months. The secondary endpoint was major adverse cardiac events (MACE). After propensity-score matching, the two groups were well matched for clinical and angiographic characteristics. Patients undergoing IVUS-guided DES implantation underwent less direct stenting, more post-dilation, and had greater cutting balloon and rotational atherectomy use. At 30 days and at 12 months, a higher rate of definite stent thrombosis was seen in the No IVUS group (0.5 vs. 1.4%; P = 0.046) and (0.7 vs. 2.0%; P = 0.014), respectively. There were no major differences in late stent thrombosis and MACE (14.5 vs. 16.2%; P = 0.33) at 12 month follow-up between the groups. Rates of death and Q-wave myocardial infarction were similar, and there was no significant difference between groups in target vessel revascularization. However, a trend was seen in favour of the IVUS group in target lesion revascularization (5.1 vs. 7.2%; P = 0.07). IVUS guidance was an independent predictor of freedom from cumulative stent thrombosis at 12 months (adjusted HR 0.5, CI 0.1-0.8; P = 0.02)., Conclusion: IVUS guidance during DES implantation has the potential to influence treatment strategy and reduce both DES thrombosis and the need for repeat revascularization.

Background: The clinical significance of intravascular ultrasound (IVUS) assessed remodeling in left main coronary artery (LMCA) lesions has not been studied. Thus, we evaluated the impact of coronary arterial remodeling on cardiac events in patients with angiographically mild LMCA disease., Methods: Two hundred thirty-six patients who underwent IVUS evaluation to determine the severity of angiographically mild LMCA lesions (diameter stenosis < 50%) were included. Negative remodeling (NR) was defined as a remodeling index (lesion/reference external elastic membrane crosssectional area [CSA]) < 0.95, intermediate remodeling (IR) as between 0.95-1.05, and positive remodeling (PR) as > 1.05., Results: NR was observed in two-thirds of patients (156/236). NR lesions were more proximal in location (45.6% vs. 25.0%; p = 0.003), less frequently associated with soft plaque morphology (23.1% vs. 43.8%; p = 0.001), and had smaller plaque burdens (34.0 +/- 12.0 vs. 40.3 +/- 10.7%; p < 0.001) than IR/PR lesions. At 1-year follow up, LMCA-related cardiac events occurred in 15 patients (6.3%). NR was less frequently associated with LMCA-related cardiac events than IR/PR [6/156 (3.8%) vs. 9/80 (11.3%); p = 0.027]. In lesions associated with LMCA-related events, lumen CSA was smaller, plaque burden was larger, and the remodeling index was greater than in lesions not associated with cardiac events, but only non-NR was an independent predictor of LMCA-related events in patients with mild LMCA disease (hazard ratio 4.095; 95% CI, 1.275-13.149; p = 0.018)., Conclusions: Angiographically mild LMCA disease was more frequently associated with NR, and NR was associated with fewer LMCA-related cardiac events in patients with mild LMCA lesions.

Background: Advances in coronary artery bypass grafting (CABG) surgery and percutaneous coronary intervention (PCI) with drug-eluting stents have dramatically improved results of these procedures. The optimal treatment for patients with multivessel coronary artery disease is uncertain given the lack of prospective, randomized data reflecting current practice. This study represents a "real-world" evaluation of current technology in the treatment of multivessel coronary artery disease., Methods and Results: A total of 1680 patients undergoing revascularization for multivessel coronary artery disease were identified. Of these, 1080 patients were treated for 2-vessel disease (196 CABG and 884 PCI) and 600 for 3-vessel disease (505 CABG and 95 PCI). One-year mortality, cerebrovascular events, Q-wave myocardial infarction, target vessel failure, and composite major adverse cardiovascular and cerebrovascular events were compared between the CABG and PCI cohorts. Outcomes were adjusted for baseline covariates and reported as hazard ratios. The unadjusted major adverse cardiovascular and cerebrovascular event rate was reduced with CABG for patients with 2-vessel disease (9.7% CABG versus 21.2% PCI; P<0.001) and 3-vessel disease (10.8% CABG versus 28.4% PCI; P<0.001). Adjusted outcomes showed increased major adverse cardiovascular and cerebrovascular event with PCI for patients with 2-vessel (hazard ratio 2.29; 95% CI 1.39 to 3.76; P=0.01) and 3-vessel disease (hazard ratio 2.90; 95% CI 1.76 to 4.78; P<0.001). Adjusted outcomes for the nondiabetic subpopulation demonstrated equivalent major adverse cardiovascular and cerebrovascular event with PCI for 2-vessel (hazard ratio 1.77; 95% CI 0.96 to 3.25; P=0.07) and 3-vessel disease (hazard ratio 1.70; 95% CI 0.77 to 3.61; P=0.19)., Conclusions: Compared with PCI with drug-eluting stents, CABG resulted in improved major adverse cardiovascular and cerebrovascular event in patients with 2- and 3-vessel coronary artery disease, primarily in those with underlying diabetes. Coronary artery bypass surgery may be the preferred revascularization strategy in diabetic patients with multivessel coronary artery disease.

Background: Significant aorto-ostial disease is difficult to evaluate with angiography and sometimes even with intravascular ultrasound (IVUS)., Methods: We used IVUS to compare ostial lesions in the left main coronary (LMCA, n = 45) versus the right coronary artery (RCA, n = 50). IVUS measurements were performed each 1 mm beginning within the ostium and continuing to the distal reference segment. Negative remodeling was defined as a remodeling index (lesion/distal reference arterial area) < 0.95., Results: Patient age was 66 +/- 11 years in the LMCA group and 66 +/- 11 years in the RCA group; 56% of the LMCA ostial lesions and 46% of RCA ostial lesions were in males, and 35% of the LMCA ostial lesions and 20% of the RCA ostial lesions were in diabetics. With the exception of a smaller minimum lumen area (p < 0.0001) and distal reference plaque burden (p = 0.002) in ostial RCA lesions and a larger eccentricity index in ostial LMCA lesions (p = 0.001), both sites were remarkably similar. Both ostial LMCA and RCA lesions were short, had modest amounts of calcium, had modest plaque burdens, but had a marked frequency of negative remodeling (84% in LMCA and 86% in RCA; p = 1.0)., Conclusion: IVUS morphometry is similar in ostial LMCA and RCA lesions; negative remodeling is the dominant contributor to lumen compromise in both locations.

Background: Sedentary activities, such as watching television, may disrupt habituation to food cues, thereby increasing motivation to eat and energy intake., Objective: These experiments were designed to examine the effect of television watching on habituation of ingestive behavior in children., Design: In experiment 1, all children worked for access to cheeseburgers in trials 1-7 (habituating stimulus). In trials 8-10, children in the control group continued to work for cheeseburgers without any dishabituating stimuli, whereas children in the other groups received either a novel food (French fries) or television as dishabituating stimuli. Responding for food and amount of food eaten were measured. In experiment 2, all children had access to 1000 kcal of a preferred snack food. One group watched a continuous television show, and the control groups either watched no television or watched a repeated segment of a television show, which controls for the television stimulus but requires reduced allocation of attention., Results: In experiment 1, both the novel food and the television watching groups reinstated responding for food (P = 0.009) and increased the amount of energy earned (P = 0.018) above the level of the control subjects. In experiment 2, the continuous television group spent more time eating (P < 0.0001) and consumed more energy than the no television and the repeated segment groups (P = 0.007)., Conclusion: These experiments show that television watching can dishabituate eating or disrupt the development of habituation, which may provide a mechanism for increased energy intake associated with watching television.

Background: Enoxaparin is an established therapy for the treatment of patients with acute coronary syndrome (ACS), and bivalirudin is commonly used as the antithrombotic agent during percutaneous coronary intervention (PCI). This study was designed to examine the safety of switching from enoxaparin to bivalirudin in these patients., Methods: The Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes without ST-segment Elevation Undergoing Percutaneous Coronary Intervention (SWITCH) trial was a prospective, open-label, multicenter study including 91 patients who presented with an ACS without ST-segment elevation, and who had received greater than or equal to 1 dose of enoxaparin (1 mg/kg SC) within the 12 hours prior to PCI. Patients were enrolled into 3 time categories: Group 1: 0-4; Group 2: 4-8; and Group 3: 8-12 hours from last enoxaparin dose to PCI. The primary endpoint of the study was major bleeding complications., Results: Baseline characteristics and average number of enoxaparin injections prior to PCI were similar in all 91 patients and among the groups. There was no occurrence of death, Q-wave myocardial infarction (MI), or acute revascularization in any group and no incidence of intracranial or retroperitoneal bleeding. The overall rate of major bleeding (7.7%) was comparable among groups (p = 0.39), as was the incidence of periprocedural non-Q-wave MI (overall 12%; p = 0.58), irrespective of the time interval between enoxaparin and bivalirudin administration., Conclusions: Switching from enoxaparin to bivalirudin for patients with ACS undergoing PCI appears to be clinically safe without increased risk of major bleeding complications, regardless of the time of enoxaparin administration, and is safe enough to warrant testing it in larger numbers.

Objectives: The goal of this study was to use intravascular ultrasound (IVUS) to compare octogenarians versus patients <65 years of age with regard to culprit lesion morphology in acute myocardial infarction (MI)., Background: Although octogenarians represent the fastest-growing segment of our population and have a higher risk profile, they are underrepresented in therapeutic trials., Methods: Between 2002 and 2005, 42 octogenarians and 52 patients <65 years of age underwent pre-intervention IVUS within 2 days from onset of an MI. Qualitative and quantitative measurements were performed at the lesion site and at the proximal and distal references. Positive remodeling was defined as a remodeling index (lesion/mean reference arterial area) > or =1., Results: Elderly patients mostly (71%) presented with non-ST-segment elevation myocardial infarction (NSTEMI), whereas patients <65 years of age presented almost equally with ST-segment elevation myocardial infarction (STEMI) and NSTEMI (56% vs. 44%). The frequency of rupture/dissection was greater in the <65-year-old group (32% vs. 9%, p = 0.009), and culprit lesions contained more thrombus in this group (14% vs. 2%, p = 0.04). Conversely, in octogenarians, lesions were predominantly calcified (57% vs. 10%, p < 0.001) and longer (20.9 +/- 7.8 mm vs. 16.6 +/- 6.1 mm, p = 0.004) with less positive remodeling (19% vs. 56%, p < 0.001). On multivariant logistic regression analysis, age was the only independent predictor of calcified plaque (p = 0.02) and remodeling (p = 0.005)., Conclusions: Negative remodeling and calcified plaque with rare plaque ruptured were common in elderly people with acute MI. These findings may contribute to the difference in clinical presentation and may suggest a different pathophysiologic mechanism of MI in octogenarians.

Objectives: We aimed to compare the clinical outcomes of dialysis versus nondialysis patients after coronary drug-eluting stent (DES) implantation., Background: The revascularization of ischemic heart disease in dialysis patients has remained controversial due to consistent exclusion of this population from major trials, especially in the context of percutaneous coronary interventions (PCI) with DES., Methods: We analyzed the data on 3,442 consecutive patients who underwent PCI and DES implantation since March 2003. Periprocedural events, 1- and 6-month clinical outcomes were then compared between dialysis (n = 72) and nondialysis patients (n = 3,370)., Results: Baseline characteristics revealed a higher prevalence of female gender (p = 0.03), African Americans (p < 0.001), hypertension (p < 0.001), diabetes mellitus (p < 0.001), number of diseased vessels (p = 0.04), lower ejection fraction (p < 0.001), and a higher prevalence of acute myocardial infarction (MI) (p = 0.04) in dialysis patients. Nondialysis patients showed more history of smoking (p < 0.001) and obesity (p = 0.02). Procedural success was higher (p = 0.05), while there was a trend toward a lower mortality rate, in the nondialysis group during hospitalization. At 6 months, the restenosis rate was low and comparable, but mortality occurred more often (16% vs. 3.8%; p < 0.001) in dialysis patients. Multivariate analysis revealed cardiogenic shock (p = 0.04) to be an independent predictor of mortality., Conclusions: PCI with DES in dialysis patients is safe and feasible, with a similar reduction of repeat revascularization when compared with nondialysis patients. There was, however, a higher incidence of mortality in dialysis patients at 6 months, mostly influenced by contributing comorbidities and more severe conditions at presentation.

Background: Stent thrombosis (ST) is a serious complication of drug-eluting stent (DES) implantation regardless of the timing (acute, subacute, or late). The correlates of ST with DES are not yet completely elucidated., Methods and Results: From a total cohort of 2974 consecutive patients treated with DES since April 2003, we identified 38 patients who presented with angiographic evidence of ST (1.27%). The ST occurred acutely in 5 patients, subacutely (< or =30 days) in 25 patients, and late (>30 days) in 8 patients. The clinical, angiographic, and procedural variables of these patients were compared with the remaining 2936 consecutive patients who underwent DES implantation and did not experience ST during a follow-up of 12 months. Logistic regression analysis was conducted to determine the correlates of ST. Compared with patients without ST, patients with ST had a higher frequency of diabetes, acute postprocedural renal failure, and chronic renal failure. There were more bifurcation lesions, type C lesions, and a trend for smaller-diameter stents. Discontinuation of clopidogrel was higher in these patients (36.8% versus 10.7%; P<0.0001). The mean duration to ST from the stent implantation was 8.9+/-8.5 days in subacute and 152.7+/-100.4 days in late thrombosis cases. Mortality was significantly higher in patients with ST compared with those without ST at 6 months (31% versus 3%; P<0.001). Multivariate analysis detected cessation of clopidogrel therapy, renal failure, bifurcation lesions, and in-stent restenosis as significant correlates of ST (P<0.05)., Conclusions: ST continues to be a serious complication of contemporary DES use. Careful management is warranted in patients with renal failure and in those undergoing treatment for in-stent restenosis and bifurcations. Special focus on clopidogrel compliance may minimize the incidence of ST after DES implantation.

Recurrent in-stent restenosis (ISR) following intracoronary radiation therapy (IRT) continues to be a therapeutic challenge. The present study aims to evaluate the clinical outcomes of patients who were treated with drug-eluting stent (DES) implantation versus repeat IRT for recurrent ISR after brachytherapy failure. A cohort of 88 patients who were previously treated with brachytherapy for ISR and presented with angina and recurrence of angiographic restenosis were evaluated for treatment with either DES [sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES); n = 34] or percutaneous coronary intervention (PCI) and repeat radiation (gamma or beta radiation; n = 54). The two groups had similar baseline clinical and angiographic characteristics. The in-hospital outcomes were similar between both groups. At long-term follow-up of 9.7 +/- 4.1 months for the DES group and 10.3 +/- 3.5 months for the repeat IRT group, there were no deaths or myocardial infarctions (MI). There was a trend toward more target vessel revascularization-major adverse cardiac events (TVR-MACE) in the DES group (p = 0.09). In addition, the patients in the DES group had a significantly lower survival rate compared to those in the repeat IRT group (p = 0.018). For patients who had recurrent ISR following IRT, either DES implantation or repeat radiation is safe and is associated with excellent immediate outcomes. Yet, at long-term follow-up, repeat IRT was associated with less recurrences and need for repeat revascularization when compared to DES implantation. Therefore, repeat IRT should be considered as an option for this difficult patient subset.

Background: The pattern of saphenous vein graft (SVG) calcification before percutaneous intervention has not been studied., Methods and Results: We used diagnostic and preintervention intravascular ultrasound (IVUS) to determine the incidence and magnitude of SVG calcification in 334 SVG lesions in 274 consecutive patients. Calcium was found in 133 SVGs (40%). Calcium was uniformly distributed among 48 lesion sites (14%), 43 proximal references (13%), and 42 distal references (13%). Calcium was superficial in 20 (40%) and deep in 28 (60%). Over the entire length of the SVGs, the maximum arc and length of calcium (in calcium-containing SVGs) averaged 174+/-107 degrees and 6.8+/-4.8 mm, respectively. In calcium-containing SVGs, lesion site arc and length of calcium measured 151+/-107 degrees and 4.1+/-3.7 mm, similar to the proximal and distal references (175+/-121 degrees and 4.0+/-2.3 mm and 177+/-121 degrees and 4.1+/-2.5 mm, respectively). Graft age (7.5+/-4.7 versus 10.5+/-4.7 years, P<0.0001), insulin-treated diabetes mellitus (40% versus 60%, P=0.02), and tobacco use (44% versus 55%, P=0.06) were clinical independent predictors of SVG calcification., Conclusions: Sixty-five percent of calcium-containing SVGs had reference calcium in the absence of lesion calcium. Calcium was located primarily in SVG wall and not at the plaque. These data suggest that SVG calcium is not just part of lesion formation and maturation. SVG calcium occurred more commonly in older grafts, in insulin-treated diabetic patients, and in smokers.

Pre-treatment of patients with clopidogrel prior to coronary angiography (CAG) and possible percutaneous coronary intervention (PCI) is a standard practice. Candidates for coronary artery bypass surgery (CABG) are discharged or remain in the hospital until CABG after clopidogrel is discontinued. We investigated whether any differences exist in the rates of surgical complications and outcomes between these two groups of patients. We conclude that continued hospitalization of clopidogrel pre-treated patients does not confer any safety benefit with regard to post-operative complications and 30-day mortality. Discharging these patients after CAG may reduce hospitalization costs.

Whether percutaneous coronary intervention (PCI) alone is safe in patients with moderate or severe aortic stenosis (AS) and coexisting coronary artery disease (CAD), and whether aortic valve replacement (AVR) can be deferred in patients with moderate AS by undergoing PCI alone is not known. We conducted a retrospective study of surgically inoperable patients with AS who underwent PCI (moderate AS, n = 28; and severe AS, n = 28) and compared to those with AVR (n = 55). The clinical characteristics, procedural complications, in-hospital and long-term clinical outcomes of PCI were compared. Baseline and procedural characteristics were similar except that lower age, hypertension, and renal impairment were seen in the AVR group. In-hospital complications were comparable among the 3 groups. Six-month and 1-year rates of myocardial infarction (MI), non-Q-wave MI, death and out-of-hospital death were similar between AVR and moderate AS patients (p = NS) and significantly high (p < 0.04) in patients with severe AS. On multivariate analysis, severe AS was the only significant predictor of 6-month and 1-year mortality. Our study suggests that PCI is safe in patients with moderate AS and coexisting CAD but is associated with poor outcomes in patients with severe AS.

Objectives: The aim of this study was to establish safety and feasibility of oral Rapamycin at two doses-2 mg and 5 mg-in achieving low rates of repeat target lesion revascularization (TLR) in de novo native coronary artery lesions., Background: Drug-eluting stents have shown the ability to limit restenosis. Oral Rapamycin is an alternative strategy that can target multiple coronary lesions suitable for treatment with any approved metal stent and at potentially lower cost., Methods: The Oral Rapamune to Inhibit Restenosis (ORBIT) study is an open-label study of 60 patients with de novo lesions treated with bare metal stents in up to two vessels. After a loading dose of 5 mg, patients received a daily dose of 2 mg (n = 30) and 5 mg (n = 30) for 30 days. Six-month angiographic, intravascular ultrasound (IVUS), and clinical follow-up were conducted., Results: Baseline clinical and procedural characteristics were similar: 10% of patients in the 2-mg group and 30% in the 5-mg group did not complete the course; 43% in the 2-mg group and 66% in the 5-mg group had side effects. At six-month follow-up, late loss (0.6 +/- 0.5 mm vs. 0.7 +/- 0.5 mm; p = NS), in-stent binary restenosis (7.1% vs. 6.9%; p = NS), in-stent percent volume obstruction by IVUS (29% vs. 24%; p = NS), and clinically driven TLR (14.3% vs. 6.9%; p = NS) were similar in 2-mg and 5-mg groups., Conclusions: Oral Rapamycin for the prevention of restenosis is safe, feasible, and associated with low rates of repeat revascularization. Although associated with certain side effects, it may be considered for patients undergoing multivessel stents if proven in larger randomized studies.

Background: The Washington Radiation for In-Stent Restenosis Trial is a double-blinded randomized study evaluating the effects of intracoronary radiation therapy (IRT) in patients with in-stent restenosis (ISR)., Methods and Results: One hundred thirty patients with ISR (100 native coronary and 30 vein grafts) underwent percutaneous transluminal coronary angioplasty, laser ablation, rotational atherectomy, or additional stenting (36% of lesions). Patients were randomized to either 192-Iridium IRT or placebo, with a prescribed dose of 15 Gy to a 2-mm radial distance from the center of the source. Angiographic restenosis (27% versus 56%, P=0.002) and target vessel revascularization (26% versus 68%, P<0.001) were reduced at 6 months in patients treated with IRT. Between 6 and 60 months, patients treated with IRT compared with placebo had more target lesion revascularization (IRT, 21.6% versus placebo, 4.7%; P=0.04) and target vessel revascularization (IRT, 21.5% versus placebo, 6.1%; P=0.03). At 5 years, the major adverse cardiac event rate was significantly reduced with IRT (46.2% versus 69.2%, P=0.008)., Conclusions: In the Washington Radiation for In-Stent Restenosis Trial, patients with ISR treated with IRT using 192-Iridium had a reduction in the need for repeat target lesion and vessel revascularization at 6 months and 5 years.

Background: Intracoronary radiation therapy (IRT) is the only proven treatment for in-stent restenosis (ISR). It is, however, associated with a significant failure rate. The present study evaluated the outcomes of patients who underwent repeat intracoronary radiation for recurrent ISR., Methods and Results: Fifty-one consecutive patients who failed a previous radiation treatment, presented with angina and angiographic evidence of ISR, and were treated with percutaneous coronary intervention (PCI) and repeat radiation to the same segment were studied. Twenty-five patients were treated with gamma radiation in a dose of 15 Gy, and 26 were treated with beta radiation doses of 18.3 to 23 Gy. The mean cumulative dose for this cohort was 39.5+/-11.9 Gy (range, 29 to 75.6 Gy). The outcomes of those patients were compared with outcomes of 299 patients who also failed initial radiation but were treated with repeat conventional PCI to a previously irradiated segment without repeat radiation. At 9 months after treatment, the repeat-IRT group had lower rates of target lesion revascularization (23.5% versus 54.6%; P<0.001) and major adverse cardiac events, including target vessel revascularization (29.4% versus 61.3%; P<0.001). At 9 months, patients with repeat IRT were free of angiographic and clinical events related to the radiation therapy., Conclusions: Repeat gamma or beta radiation to treat failed IRT for ISR after conventional PCI is safe and effective at 9 months and should be considered as a therapeutic option for this difficult patient subset.

Background: Previous studies have reported diffuse destabilization of atherosclerotic plaques in acute myocardial infarction (AMI)., Methods and Results: We used intravascular ultrasound (IVUS) to assess 78 coronary arteries (38 infarct-related arteries [IRAs] with culprit and nonculprit lesions and 40 non-IRAs) from 38 consecutive AMI patients. IVUS analysis included qualitative and quantitative measurements of reference and lesion external elastic membrane (EEM), lumen, and plaque plus media (P&M) area. Positive remodeling was defined as lesion/mean reference EEM >1.0. Culprit lesions were identified by a combination of ECG, wall motion abnormalities (ventriculogram or echocardiogram), scintigraphic perfusion defects, and coronary angiogram. Culprit lesions contained more thrombus (23.7% versus 3.4% in nonculprit IRA plaques and 3.1% in non-IRA plaques; P=0.0011). Culprit lesions were predominantly hypoechoic (63.2% versus 37.9% of nonculprit IRA plaques and 28.1% of non-IRA plaques; P=0.0022). Culprit lesions were longer (17.5+/-10.1, 9.8+/-4.0, and 10.3+/-5.7 mm, respectively; P<0.0001), had larger EEM area (15.0+/-6.0, 11.5+/-5.7, and 12.6+/-5.6 mm2, respectively; P=0.0353) and P&M area (13.0+/-6.0, 7.5+/-3.7, 9.3+/-4.3 mm2, respectively; P<0.0001), smaller lumens (2.0+/-0.9, 4.1+/-3.1, and 3.4+/-2.5 mm2, respectively; P=0.0009), and more positive remodeling (79.4%, 59.0%, and 50.8%, respectively; P=0.0155). The frequency of plaque rupture/dissection was greater in culprit, nonculprit IRA, and non-IRA plaques in AMI patients than in a control group of chronic stable angina patients with multivessel IVUS imaging., Conclusions: Culprit plaques have more markers of instability (thrombus, positive remodeling, and large plaque mass); however, these markers of instability are not typically found elsewhere. This suggests that the vascular event in AMI patients is determined by local pre-event lesion morphologies.

Background: The Washington Radiation for In-Stent Restenosis Trial for long lesions (Long WRIST) was designed to determine the safety and efficacy of vascular brachytherapy for the treatment of diffuse in-stent restenosis., Methods and Results: A total of 120 patients with diffuse in-stent restenosis in native coronary arteries (lesion length, 36 to 80 mm) were randomized for either radiation with 192Ir with 15 Gy at 2 mm from the source axis or placebo. After enrollment, 120 additional patients with the same inclusion criteria were treated with 192Ir with 18 Gy and included in the Long WRIST High Dose registry. Antiplatelet therapy was initially prescribed for 1 month and was extended to 6 months in the last 60 patients of the Long WRIST High Dose registry. At 6 months, the binary angiographic restenosis rate was 73%, 45%, and 38% in the placebo, 15 Gy, and 18 Gy radiated groups, respectively (P<0.05). At 1 year, the primary clinical end point of major cardiac events was 63% in the placebo group and 42% in the radiated group with 15 Gy (P<0.05). The major cardiac event rate was further reduced with 18 Gy (22%; P<0.05 versus 15 Gy). Late thrombosis was 12%, 15%, and 9% in the placebo group, 15 Gy group with 1 month of antiplatelet therapy, and 18 Gy group with 6 months of antiplatelet therapy, respectively., Conclusions: Vascular brachytherapy with 192Ir is safe and reduces the rate of recurrent restenosis in diffuse in-stent restenosis. The efficacy of vascular brachytherapy on angiographic and clinical outcomes is enhanced with a radiation dose of 18 Gy and prolonged antiplatelet therapy.

Objectives: This study reports the outcome of patients who failed intracoronary radiation therapy (IRT) for the treatment of in-stent restenosis (ISR)., Background: Intracoronary radiation therapy has demonstrated a reduction in the recurrence rate of restenosis for patients with ISR. However, 10% to 30% of these patients require repeat intervention to the irradiated site., Methods: Of 961 patients who were assigned to gamma or beta radiation for the treatment of diffuse ISR, we evaluated the outcome of 282 (29%) consecutive patients who failed IRT and compared them with the 679 (71%) patients who had successful IRT. For patients who failed radiation, the mean time to the first target vessel revascularization (TVR) was 173 +/- 127 days after the index procedure and the total duration of follow-up was 494 +/- 304 days., Results: Patients who failed IRT were younger (60 +/- 10 vs. 63 +/- 11 years, p = 0.002) and had a higher incidence of restenting (51% vs. 41%, p = 0.003). The majority (55%) of the restenotic lesions after IRT failure were focal (< or =10 mm), with a mean lesion length of 11.9 +/- 1.9 mm. Of the 257 patients who had subsequent TVR after failed IRT, 68 (26%) underwent coronary artery bypass grafting and 189 (74%) underwent percutaneous coronary intervention using balloon in 61%, restenting in 26%, atheroablation in 11%, and the cutting balloon in 2% of cases. At six months, 6% of patients died, 1% had Q-wave MI, 17% had repeat TVR, and the overall rate of major adverse cardiac events was 21%., Conclusions: The predominant angiographic pattern of lesions in patients who failed IRT is focal restenosis, with these lesions responding well to conventional revascularization methods.

Objective: To compare the effects of arterial remodelling and plaque characteristics on the mechanisms of direct stenting and predilatation stenting. Direct stenting has become routine in some laboratories and differs technically from predilatation stenting., Methods: Pre- and post-interventional volumetric intravascular ultrasound (IVUS) was undertaken in 30 patients with direct stenting and in 30 with predilatation stenting of non-calcified native coronary lesions, using the same stent design and stent length. Lumen, vessel (external elastic membrane (EEM)), and plaque (plaque + media) volumes were calculated. Remodelling was determined by comparing the EEM area at the centre of the lesion with the EEM areas at proximal and distal reference sites. Plaque eccentricity was defined as the thinnest plaque diameter to the thickest plaque diameter ratio. Plaque composition was characterised as soft, mixed, or dense., Results: All volumetric IVUS changes were similar in the two groups. Pre-intervention remodelling remained uninfluenced after direct stenting, but was neutralised after predilatation stenting. Eccentric lesions responded to intervention by a greater luminal gain owing to greater vessel expansion in direct stenting. Plaque composition influenced luminal gain in direct stenting, the gain being greatest in the softest plaques; in predilatation stenting, luminal gain was equivalent but vessel expansion was greater for "dense" plaque and plaque reduction greater for "soft" plaque., Conclusions: In non-calcified lesions, the mechanisms of lumen enlargement after direct or predilatation stenting are significantly influenced by atherosclerotic remodelling, plaque eccentricity, and plaque composition.

Background: Contrast-induced nephropathy (CIN) is a recognized complication after percutaneous interventions (PCI). We sought to determine the impact of gender on incidence and clinical outcome of CIN., Methods and Results: Of a total 8,628 patients who underwent PCI, there were 1,431 (16.5%) who developed CIN (defined as > 25% rise in creatinine after PCI). Patients were followed clinically for one year. CIN was present in 23.6% of female versus 17.4% of male patients (p < 0.0001). Multivariate analysis showed that female gender (OR = 1.4, 95% CI = 1.25 1.60; p < 0.0001), pre-PCI chronic renal failure (CRF) (OR= 1.8, 95% CI = 1.53 2.10, p < 0.0001), diabetes mellitus (OR = 1.5, 95% CI = 1.34 1.70; p < 0.0001), age (OR = 1.01, 95% CI = 1.01 1.02, p < 0.0001), and hypertension (OR = 1.2, 95% CI = 1.06 1.36, p = 0.0035) were independent predictors of CIN. Clinical outcomes after CIN were examined in patients with or without CRF. Among patients without CRF who developed CIN, females (n = 465) had higher rates of one-year mortality, and MACE comparing to males (n = 710) without CRF (14% vs. 10% mortality, 36% vs. 30% MACE; p = 0.05 and 0.06, respectively). In patients with CRF who developed CIN, we found no significant gender differences in one-year clinical events (37% vs. 36% mortality, 42% vs. 45% MACE; p = 0.8 and 0.6, respectively). By multivariate analysis only baseline CRF, diabetes, age, functional NYHA IV class were identified as independent predictors of one-year mortality in patients with CIN after PCI., Conclusions: Female gender is an independent predictor of CIN development after PCI and a marker of worse 1-year mortality after CIN in patients without baseline CRF. After CIN is developed, pre-PCI CRF, diabetes mellitus, age, severe heart failure (not gender) are independent predictors of one-year mortality.

Objectives: This study was designed to report the clinical and angiographic correlates of plaque rupture detected by intravascular ultrasound (IVUS)., Background: Acute coronary syndromes result from spontaneous plaque rupture and thrombosis., Methods: We report 300 plaque ruptures in 257 arteries in 254 patients. Plaque ruptures were detected during pre-intervention IVUS. Standard clinical, angiographic, and IVUS parameters were collected and/or measured. One lesion per patient was analyzed., Results: Multiple ruptures were observed in 39 of 254 patients (15%), 36 in the same artery. Plaque rupture occurred not only in patients with unstable angina (46%) or myocardial infarction (MI, 33%), but also stable angina (11%) or no symptoms (11%). The tear in the fibrous cap could be identified in 157 of 254 patients; 63% occurred at the shoulder of the plaque and 37% in the center of the plaque. Thrombi were more common in patients with unstable angina or MI (p = 0.02) and in multiple ruptures (p = 0.04). The plaque rupture site contained the minimum lumen area (MLA) site in only 28% of patients; rupture sites had larger arterial and lumen areas and more positive remodeling than MLA sites. Intravascular ultrasound plaque rupture strongly correlated with complex angiographic lesion morphology: ulceration in 81%, intimal flap in 40%, thrombus in 7%, and aneurysm in 7%., Conclusions: Plaque ruptures occur with varying clinical presentations, strongly correlate with angiographic complex lesion morphology, may be multiple, and usually do not cause lumen compromise.

Background: Stroke associated with percutaneous coronary intervention (PCI) is an infrequent although devastating complication. We investigated the incidence, predictors, and prognostic impact of periprocedural stroke in unselected patients undergoing PCI., Methods and Results: A total of 9662 patients who underwent 12 407 PCIs between January 1990 and July 1999 were retrospectively studied. Stroke was diagnosed in 43 patients (0.38% of procedures). Patients with stroke were older (72+/-11 versus 64+/-11 years, P<0.001), had lower left ventricular ejection fraction (42+/-12 versus 46+/-13%, P=0.04) and more diabetes (39.5% versus 27.2%, P=0.07), and experienced a higher rate of intraprocedural complications necessitating emergency use of intra-aortic balloon pump (IABP) (23.3% versus 3.3%, P<0.001). In-hospital mortality (37.2% versus 1.1%, P<0.001) and 1-year mortality (56.1% versus 6.5%, P<0.001) were higher in patients with stroke. Compared with hemorrhagic stroke, patients with ischemic stroke had higher rate of in-hospital major adverse cardiac events (57.1% versus 25%, P=0.037). Multivariate logistic regression analysis identified emergency use of IABP as the strongest predictors for stroke (OR=9.6, CI 3.9 to 23.9, P<0.001), followed by prophylactic use of IABP (OR=5.1), age >80 years (OR=3.2, compared with age <50 years), and vein graft intervention (OR=2.7)., Conclusions: Stroke associated with contemporary PCI is associated with substantial increased mortality. Elderly patients who experience intraprocedural complications necessitating the use of IABP are at particularly high risk.

Objectives: The purpose of this study was to examine the effect of intracoronary radiation therapy (IRT) in diabetic patients with in-stent restenosis (ISR)., Background: Diabetic patients are at an increased risk for restenosis, repeat revascularization procedures and late mortality after percutaneous coronary interventions and stenting. Intracoronary radiation therapy, utilizing both gamma and beta-emitters, has been shown to reduce the rate of ISR., Methods: The study group consisted of 749 consecutive patients with ISR who were treated with either IRT or placebo in randomized trials and registries at our center. Diabetic patients (252 radiation and 51 placebo) were compared with nondiabetic patients (371 radiation and 75 placebo)., Results: In-hospital outcomes were similar between diabetic and nondiabetic patients treated with and without radiation. At six-month clinical and angiographic follow-up, there was a significant reduction in the binary restenosis (63.8% vs. 15.7%, p < 0.0001), target lesion revascularization (66.7% vs. 17.6%, p < 0.0001) and target vessel revascularization (TVR) (70.6% vs. 22.9%, p < 0.0001) rates in diabetic patients treated with radiation compared to placebo. Comparisons between the placebo arms detected a trend towards higher restenosis (63.8% vs. 48.4% p = 0.13) and TVR (70.6% vs. 56.0%, p = 0.14) in diabetic versus nondiabetic patients. In contrast, diabetic and nondiabetic patients treated with IRT experienced similar restenosis (15.6% vs. 10.7% p = 0.33) and TVR (22.9% vs. 28.2% p = 0.41) rates., Conclusions: In diabetic patients with ISR, intracoronary radiation significantly reduced the recurrence of ISR compared to placebo. Additionally, similar rates of restenosis and revascularization procedures were achieved in irradiated diabetic and nondiabetic patients. In view of these results, IRT should be considered as a valuable therapeutic alternative in all diabetic patients with ISR.

Background: Intramural hematomas during percutaneous coronary intervention (PCI) have not been well studied., Methods and Results: We used intravascular ultrasound to determine the incidence, morphology, and clinical features of post-PCI intramural hematomas. In 905 patients with 1025 consecutive native coronary artery, non-in-stent restenosis lesions undergoing PCI, 72 hematomas were detected in 69 arteries in 68 patients. The incidence of intramural hematomas per artery was 6.7% (69 of 1025); 36% (26 of 72) involved the proximal reference artery, 18% (13 of 72) were confined to the lesion, and 46% (33 of 72) involved the distal reference artery. The entry site from the lumen into the hematoma was identified in 86% of hematomas (62 of 72) and had the appearance of a dissection into the media. Conversely, a re-entry site was identifiable in only 8% (6 of 72). The axial extension of the hematoma was distal in 63% and proximal in 37%. In 60% of the hematomas (42 of 72) the angiogram had the appearance of a dissection; in 11% (8 of 72), it appeared to be a new stenosis; and in 29% (22 of 72), no significant abnormality was detected. Non-Q-wave myocardial infarctions occurred in 26% of patients (17 of 65). In 3 patients, the creatine kinase-MB was not measured during the hospital stay. Repeat revascularization occurred in 2 patients in-hospital, 2 additional patients at 1 month, and 8 additional patients at 1 year. There were 3 sudden deaths at 1 year., Conclusions: Intravascular ultrasound identified intramural hematomas after 6.7% of PCIs. The mechanism appeared to be a dissection into the media where blood accumulated because of a lack of re-entry. A third of ultrasound-identified hematomas showed no angiographic abnormalities. There was a high rate of non-Q-wave myocardial infarction, need for repeat revascularization, and sudden death in patients with hematomas.