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Background: In the drug eluting stent (DES) era, repeat in-stent restenosis (ISR) of the same coronary lesion, despite percutaneous coronary intervention (PCI), is a rare but challenging problem that has not been reported. We aim to describe what we propose as the occurrence of "resistant"-ISR (R-ISR) in the DES era, including angiographic patterns and outcomes., Methods: We defined R-ISR as the recurrence of an ISR episode after successful treatment of the same lesion. We identified 276 consecutive patients with 291 lesions who had R-ISR between May 2003 and June 2012. Quantitative coronary angiography (QCA) was performed for the first and second ISR episodes. Outcomes at one year, including death, myocardial infarction (MI), and target lesion failure (TLF), were analyzed., Results: Patients with R-ISR had a high frequency of diabetes (62%), chronic kidney disease (39%), bifurcation lesions (51%), and moderate to severe calcified lesions (52%). The most common pattern of R-ISR was focal (77%). R-ISR lesions were treated with DES implantation (55%) or balloon-only strategy (45%). The mortality rate and TLF at 2-years were 9.3% and 51% respectively. The overall 2-year TLF rate did not vary with the originally implanted stent, angiographic pattern (focal versus diffuse), or revascularization strategy., Conclusions: R-ISR appears to consist predominantly of focal lesions and occurs in patients at high clinical and angiographic risk, conceivably owing to their unique diabetic and coronary calcification profile. Clinical outcomes are suboptimal irrespective of angiographic pattern or treatment strategy, indicating the recalcitrant nature of the disease, and need for aggressive treatment of cardiovascular risk factors and novel interventional approaches. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases., Competing Interests: The authors have declared that no competing interests exist.

Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention., (Copyright © 2016, American Association for the Advancement of Science.)

Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. 'Transitioning' cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events.

Transcatheter aortic valve replacement is a viable alternative for patients who are too high risk for traditional surgical aortic valve replacement, but it is not without risk of vascular complication. We report a case in which a hybrid stent and bypass graft technique was used to repair a complete iliofemoral artery avulsion after a transcatheter aortic valve replacement procedure. We believe that particular caution should be taken with patients with peripheral arterial disease in access vessels. Access vessel diameter must be considered in planning of procedures, and preprocedural preparation for potential major vascular complications is crucial for reducing morbidity and mortality.

Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT(+), PDGFRα(+), ISL1(+)and SCA1(+)cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair., (© 2016. Published by The Company of Biologists Ltd.)

Cardiovascular disease is the leading cause of mortality in the world, and the increasing burden is largely a consequence of modifiable behavioral risk factors that interact with genomics and the environment. Continuous cardiovascular health promotion and disease prevention throughout the lifespan is critical, and the family is a central entity in this process. In this review, we describe the potential rationale and mechanisms that contribute to the importance of family for cardiovascular health promotion, focusing on: 1) mutual interdependence of the family system; 2) shared environment; 3) parenting style; 4) caregiver perceptions; and 5) genomics. We conclude that family-based approaches that target both caregivers and children, encourage communication among the family unit, and address the structural and environmental conditions in which families live and operate are likely to be the most effective approach to promote cardiovascular health. We describe lessons learned, future implications, and applications to ongoing and planned studies., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac fibrosis (CF) is associated with increased ventricular stiffness and diastolic dysfunction and is an independent predictor of long-term clinical outcomes of patients with heart failure (HF). We previously showed that the matricellular CCN5 protein is cardioprotective via its ability to inhibit CF and preserve cardiac contractility., Objectives: This study examined the role of CCN5 in human heart failure and tested whether CCN5 can reverse established CF in an experimental model of HF induced by pressure overload., Methods: Human hearts were obtained from patients with end-stage heart failure. Extensive CF was induced by applying transverse aortic constriction for 8 weeks, which was followed by adeno-associated virus-mediated transfer of CCN5 to the heart. Eight weeks following gene transfer, cellular and molecular effects were examined., Results: Expression of CCN5 was significantly decreased in failing hearts from patients with end-stage heart failure compared to nonfailing hearts. Trichrome staining and myofibroblast content measurements revealed that the established CF had been reversed by CCN5 gene transfer. Anti-CF effects of CCN5 were associated with inhibition of the transforming growth factor beta signaling pathway. CCN5 significantly inhibited endothelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, which are 2 critical processes for CF progression, both in vivo and in vitro. In addition, CCN5 induced apoptosis in myofibroblasts, but not in cardiomyocytes or fibroblasts, both in vivo and in vitro. CCN5 provoked the intrinsic apoptotic pathway specifically in myofibroblasts, which may have been due the ability of CCN5 to inhibit the activity of NFκB, an antiapoptotic molecule., Conclusions: CCN5 can reverse established CF by inhibiting the generation of and enhancing apoptosis of myofibroblasts in the myocardium. CCN5 may provide a novel platform for the development of targeted anti-CF therapies., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study is to compare the relative merits of optical coherence tomography (OCT), intravascular ultrasound (IVUS), and near infrared spectroscopy (NIRS) in patients with coronary artery disease for the prediction of periprocedural myocardial infarction (MI)., Background: Although several individual intravascular imaging modalities have been employed to predict periprocedural MI, it is unclear which of the imaging tools would best allow prediction of this complication., Methods: We retrospectively analyzed 110 patients who underwent OCT, IVUS, and NIRS. Periprocedural MI was defined as a post-procedural cardiac troponin I (cTnI) elevation above 3× the upper limit of normal; analysis was also performed for cTnI ≥5× the upper limit of normal., Results: cTnI ≥3× was observed in 10 patients (9%) and 8 patients had cTnI ≥5×. By OCT, minimum cap thickness was significantly lower (55 vs. 90 μm, p < 0.01), and the plaque burden by IVUS (84 ± 9% vs. 77 ± 8%, p < 0.01) and maximum 4-mm lipid core burden index by NIRS (556 vs. 339, p < 0.01) were greater in the cTnI ≥3× group. Multivariate logistic regression analysis identified cap thickness as the only independent predictor for cTnI ≥3× the upper limit of normal (odds ratio [OR]: 0.90, p = 0.02) or cTnI ≥5× (OR: 0.91, p = 0.04). If OCT findings were excluded from the analysis, plaque burden (OR: 1.13, p = 0.045) and maximum 4-mm lipid core burden index (OR: 1.003, p = 0.037) emerged to be the independent predictors., Conclusions: OCT-based fibrous cap thickness is the most important predictor of periprocedural MI. In the absence of information about cap thickness, NIRS lipid core or IVUS plaque burden best determined the likelihood of the periprocedural event., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key "drivers" of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the efficacy of hemodynamic support using Impella 2.5 (IR2.5) vs intra-aortic balloon pump (IABP) in patients with 3-vessel coronary artery disease (3VD)., Background: PROTECT II demonstrated favorable 90-day outcomes in patients with impaired LVEF and left main or 3VD undergoing PCI with hemodynamic support with IR2.5 compared to IABP. It is unclear if this was due to a specific benefit in a patient sub-population and if certain patients may derive particular benefit from PCI with IR2.5 support., Methods: Patients in PROTECT II were stratified upon enrollment into the left main/last patent vessel or 3VD subgroups and randomized to IR2.5 or IABP within those groups. Patients in the 3VD substratum were required to have LVEF ≤30%., Results: Among the 3VD subgroup (n = 325 patients; IR2.5 167, IABP 158) patients were well matched, except for prior heart failure or CABG, which were more common in the IR2.5 group (both P ≤ 0.01). Mean number of lesions treated was 3.0 ± 1.5 vs. 2.9 ± 1.4 (P = 0.61). At 30 days after PCI, patients that received IR2.5 compared to IABP support trended toward a reduction in incidence of major adverse events (MAE): 32.9% vs. 42.4% (P = 0.078). At 90 days after PCI, there was a significant difference favoring IR2.5 for incidence of MAE: 39.5% vs. 51.0% (P = 0.039), with this effect being consistent across multiple clinical subgroups. Use of IR2.5 was an independent predictor of improved 90-day outcomes., Conclusions: Patients with 3VD and reduced LVEF show improved outcomes when PCI is performed with IR2.5 hemodynamic support., (© 2014, Wiley Periodicals, Inc.)

Aims: To evaluate the relationship between lipid content and plaque morphometry as well as the process of lesion progression and regression in patients with significant coronary artery disease., Methods and Results: The present study, using data from the YELLOW trial, was conducted in patients having significant coronary lesions (fractional flow reserve <0.8) who underwent serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) at baseline and after 7 weeks. For each coronary plaque (≥50% plaque burden that was ≥5 mm in length), we evaluated plaque characteristics and the extent of lipid-rich plaque [LRP, defined as the 4 mm long segment with the maximum lipid-core burden index (maxLCBI4 mm)] on NIRS. Among 66 patients (age 63.0 ± 10.1 years; 82% statin use at baseline), 94 plaques were identified. The extent of LRP at baseline was positively correlated with IVUS plaque burden (r = 0.317, P = 0.002). A large LRP (maxLCBI4 mm ≥500) was present only in plaques with a large plaque burden (≥70%). Multivariate analysis demonstrated that plaque burden was the best predictor of the extent of LRP (P < 0.001). In lesions with a large plaque burden and a large amount of LRP at baseline, a reduction in LRP was seen in all lesions in patients receiving intensive statin therapy (P = 0.004) without a significant change in plaque burden., Conclusions: Coronary lesions containing a large amount of LRP also had a large plaque burden. Short-term regression of LRP (without a change in plaque burden) was observed mainly in plaques with a large plaque burden and a large amount of LRP at baseline., Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT01567826., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Percutaneous coronary intervention (PCI) of true bifurcation lesions (Medina classification 1, 1, 1; 1, 0, 1; or 0, 1, 1) is challenging and may involve either a 1-stent strategy with provisional side branch stenting, or a 2-stent strategy. Diabetes mellitus is associated with greater atherosclerotic burden and higher incidence of bifurcation lesions, and unfavorable outcomes after PCI. It is unknown whether use of newer everolimus-eluting stent (EES) implantation impacts relative outcomes of 1-stent and 2-stent strategies in patients with diabetes., Methods: We performed a retrospective analysis of consecutive patients with diabetes mellitus and complex true bifurcation lesions (side branch diameter >2.0 mm) who underwent PCI with EES between February 2010 and December 2011. We grouped subjects based on initial treatment to a 1-stent (n = 81) or 2-stent (n = 54) strategy, and compared baseline characteristics, quantitative coronary angiography, and 1-year major adverse cardiovascular event (MACE) rates, defined as death, myocardial infarction, target lesion revascularization (TLR), or target vessel revascularization (TVR)., Results: Baseline characteristics were well matched. A 2-stent strategy was associated with larger side-branch reference vessel diameter at baseline and post PCI. In-hospital events included 1 periprocedural myocardial infarction in each group and no deaths. At 1 year, there was no significant difference between 1-stent and 2-stent strategies in TVR rates (6.2% vs 3.7%; P=.53), TLR (both 3.7%; P>.99), or MACE (7.4% vs 3.7%; P=.37)., Conclusion: In this series of diabetic patients undergoing complex bifurcation PCI using EES implantation, there was no difference between 1-stent and 2-stent strategies with respect to ischemic events at 1 year.

The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50 year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply., (Copyright © 2014. Published by Elsevier B.V.)

Background: Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype., Methods and Results: Carotid (n=10) and coronary (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology. Analysis of asTF expression and cell type-specific expression revealed a strong expression and colocalization of asTF with macrophages and neovessels within complicated, but not uncomplicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via hypoxia-inducible factor-1α upregulation through integrins and activation of phosphatidylinositol-3-kinase/Akt and mitogen-activated protein kinase pathways. Hypoxia-inducible factor-1α upregulation by asTF also was associated with increased vascular endothelial growth factor expression in primary human endothelial cells, and vascular endothelial growth factor-Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization after carotid wire injury in ApoE(-/-) mice., Conclusions: The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Here, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the hypoxia-inducible factor-1/vascular endothelial growth factor signaling. This mechanism may be relevant to neovascularization and the progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated versus uncomplicated human carotid and coronary plaques., (© 2014 American Heart Association, Inc.)

Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially sudden cardiac death. Although the classic angiographic "string of beads" that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: We sought to assess if bivalirudin use during balloon aortic valvuloplasty (BAV) would affect clinical outcomes compared with heparin., Methods and Results: We compared the outcomes of consecutive patients who underwent elective or urgent BAV with intraprocedural use of bivalirudin or heparin at two high-volume centres. All in-hospital events post BAV were adjudicated by an independent, blinded clinical events committee. Of 427 patients, 223 patients (52.2%) received bivalirudin and 204 (47.8%) received heparin. Compared with patients who received heparin, patients who received bivalirudin had significantly less major bleeding (4.9% vs. 13.2%, p=0.003). Net adverse clinical events (NACE, major bleeding or major adverse cardiovascular events [MACE]) were also reduced (11.2% vs. 20.1%, p=0.01). There was no significant difference in the rates of MACE (mortality, myocardial infarction or stroke, 6.7% vs. 11.3%, p=0.1), or vascular complications (major, 2.7% vs. 2.0%; minor, 4.5% vs. 4.9%; p=0.83). After multivariate analysis controlling for vascular preclosure, the use of bivalirudin remained independently associated with reduced major bleeding (OR 0.37; 95% CI: 0.16 to 0.84; p=0.02) while the association was attenuated in propensity-adjusted analysis (OR 0.44, 95% CI: 0.18 to 1.07, p=0.08)., Conclusions: In this registry of patients with severe aortic stenosis, bivalirudin as compared to heparin resulted in improved in-hospital outcomes post BAV in terms of reduced major bleeding, similar MACE and reduced NACE. If verified in a randomised study and extended to the transcatheter aortic valve implantation (TAVI) population, these results might indicate a potential benefit for patients undergoing such procedures.

Aims: The presence of thin-cap fibroatheromas (TCFA) is associated with high risk of acute coronary syndrome, hence their early detection may identify high-risk patients. In the present study we investigated the ability of a combined imaging catheter with near-infrared spectroscopy (NIRS) plus intravascular ultrasound (IVUS) to detect TCFA in patients with stable coronary artery disease., Methods and Results: Optical coherence tomography (OCT) and combined NIRS-IVUS assessment were performed on identical coronary segments. IVUS analysis provided per-segment minimal cross-sectional area (CSA), plaque length (PL), plaque burden (PB), plaque volume (PV), and remodelling index (RI). OCT was used as the gold-standard reference to define TCFA (fibrous cap thickness <65 μm). Plaque lipid content was estimated by NIRS (lipid core burden index [LCBI]). OCT-defined TCFA was present in 18 of 76 segments. IVUS revealed that OCT-defined TCFA were positively remodelled lesions with greater PB and PV, smaller CSA, and longer PL, while NIRS revealed greater LCBI per 2 mm segment (LCBI2mm) (all p<0.001). Greatest accuracy for OCT-defined TCFA detection was achieved using LCBI2mm >315 with RI >1.046 as a combined criterion value., Conclusions: OCT-defined TCFA are characterised by positive vessel remodelling, high plaque burden and greater lipid core burden as assessed by dual NIRS-IVUS imaging.

Culprit lesions of patients, who have had an acute coronary syndrome commonly, are ruptured coronary plaques with superimposed thrombus. The precursor of such lesions is an inflamed thin-capped fibroatheroma. These plaques can be imaged by means of invasive techniques, such as intravascular ultrasound (and derived techniques), optical coherence tomography, and near-infrared spectroscopy. Often these patients exhibit similar (multiple) plaques beyond the culprit lesion. These remote plaques can be assessed noninvasively by computed tomographic angiography and MRI and also using invasive imaging. The detection of these remote plaques is not only feasible but also in natural history studies have been associated with clinical coronary events. Different systemic pharmacological treatments have been studied (mostly statins) with modest success and, therefore, newer approaches are being tested. Local treatment for such lesions is in its infancy and larger, prospective, and randomized trials are needed. This review will describe the pathological and imaging findings in culprit lesions of patients with acute coronary syndrome and the assessment of remote plaques. In addition, the pharmacological and local treatment options will be reviewed., (© 2014 American Heart Association, Inc.)

Objectives: To compare the outcomes of initial one-stent (1S) versus dedicated two-stent (2S) strategies in complex bifurcation percutaneous coronary intervention (PCI) using everolimus-eluting stents (EES)., Background: PCI of true bifurcation lesions is technically challenging and historically associated with reduced procedural success and increased restenosis. Prior studies comparing initial one-stent (1S) versus dedicated two-stent (2S) strategies using first-generation drug-eluting stents have shown no reduction in ischemic events and more complications with a 2S strategy., Methods: We performed a retrospective study of 319 consecutive patients undergoing PCI at a single referral center with EES for true bifurcation lesions, defined by involvement of both the main vessel (MV) and side branch (SB). Baseline, procedural characteristics, quantitative coronary angiography and clinical outcomes in-hospital and at one year were compared for patients undergoing 1S (n=175) and 2S (n=144) strategies., Results: Baseline characteristics were well-matched. 2S strategy was associated with greater SB acute gain (0.65±0.41 mm vs. 1.11±0.47 mm, p<0.0001). In-hospital serious adverse events were similar (9% with 2S vs. 8% with 1S, p=0.58). At one year, patients treated by 2S strategy had non-significantly lower rates of target vessel revascularization (5.8% vs. 7.4%, p=0.31), myocardial infarction (7.8% vs. 12.2%, p=0.31) and major adverse cardiovascular events (16.6% vs. 21.8%, p=0.21)., Conclusion: In this study of patients undergoing PCI for true coronary bifurcation lesions using EES, 2S strategy was associated with superior SB angiographic outcomes without excess complications or ischemic events at one year., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Atherosclerosis research has classically followed 2 intertwining lines of investigation concerning atherosclerosis as a local process (the "high-risk plaque") and as a systemic disease (the "high-risk patient"). Over time, the weight of attention has swung, like a pendulum, between these 2 related foci. With optimal medical therapy and attention to risk factors firmly established as fundamental aspects of management, in the past year, we have nevertheless perceived a shift in the pendulum toward renewed focus on the local plaque. We contend that this shift results from a convergence of major advances in understanding the biology of plaque progression, novel sophisticated invasive and noninvasive imaging modalities for the in vivo characterization of plaque composition and inflammation, and emerging data and technologies that have renewed interest in locally targeted interventions. Here, we review the dynamic and exciting progress that has occurred over the last 12 months in this arena, while acknowledging future work that remains to be done to refine and validate new imaging modalities and therapies., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Adeno-associated virus (AAV)-based vectors are promising vehicles for therapeutic gene delivery, including for the treatment for heart failure. It has been demonstrated for each of the AAV serotypes 1 through 8 that inhibition of the proteasome results in increased transduction efficiencies. For AAV9, however, the effect of proteasome inhibitors on in vivo transduction has until now not been evaluated. Here we demonstrate, in a well-established rodent heart failure model, that concurrent treatment with the proteasome inhibitor bortezomib does not enhance the efficacy of AAV9.SERCA2a to improve cardiac function as examined by echocardiography and pressure volume analysis. Western blot analysis of SERCA2a protein and reverse transcription-PCR of SERCA2a mRNA demonstrated that bortezomib had no effect on either endogenous rat SERCA2a levels nor on expression levels of human SERCA2a delivered by AAV9.SERCA2a. Similarly, the number of AAV9 genomes in heart samples was unaffected by bortezomib treatment. Interestingly, whereas transduction of HeLa cells and neonatal rat cardiomyocytes by AAV9 was stimulated by bortezomib, transduction of adult rat cardiomyocytes was inhibited. These results indicate an organ/cell-type-specific effect of proteasome inhibition on AAV9 transduction. A future detailed analysis of the underlying molecular mechanisms promises to facilitate the development of improved AAV vectors.

Veins grafted into an arterial environment undergo a complex vascular remodeling process. Pathologic vascular remodeling often results in stenosed or occluded conduit grafts. Understanding this complex process is important for improving the outcome of patients with coronary and peripheral artery disease undergoing surgical revascularization. Using in vivo murine cell lineage-tracing models, we show that endothelial-derived cells contribute to neointimal formation through endothelial-to-mesenchymal transition (EndMT), which is dependent on early activation of the Smad2/3-Slug signaling pathway. Antagonism of transforming growth factor-β (TGF-β) signaling by TGF-β neutralizing antibody, short hairpin RNA-mediated Smad3 or Smad2 knockdown, Smad3 haploinsufficiency, or endothelial cell-specific Smad2 deletion resulted in decreased EndMT and less neointimal formation compared to controls. Histological examination of postmortem human vein graft tissue corroborated the changes observed in our mouse vein graft model, suggesting that EndMT is operative during human vein graft remodeling. These data establish that EndMT is an important mechanism underlying neointimal formation in interpositional vein grafts, and identifies the TGF-β-Smad2/3-Slug signaling pathway as a potential therapeutic target to prevent clinical vein graft stenosis.

There is a looming global epidemic of obesity and diabetes. Of all the end-organ effects caused by diabetes, the cardiovascular system is particularly susceptible to the biologic perturbations caused by this disease, and many patients may die from diabetes-related cardiovascular complications. Substantial progress has been made in understanding the pathobiology of the diabetic vasculature and heart. Clinical studies have illuminated the optimal way to treat patients with cardiovascular manifestations of this disease. This article reviews these aspects of diabetes and the cardiovascular system, broadly classified into diabetic vascular disease, diabetic cardiomyopathy, and the clinical management of the diabetic cardiovascular disease patient., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Generic clopidogrel recently became available in the United States and was rapidly adopted as a cost-effective alternative to the brand name formulation. However, unlike other medications, subtle differences in clopidogrel bioavailability may lead to acute consequences including stent thrombosis (ST)., Materials and Methods: We studied the incidence of acute and subacute ST during the initial period of generic clopidogrel use (June 18, 2012-September 6, 2012 [80 days]) at a single percutaneous coronary intervention (PCI) center. There were 4 definite ST cases within 30 days of successful PCI in patients receiving generic clopidogrel, which were compared to historic control ST cases from 80 days prior to generic clopidogrel use and for 3 years from June 18, 2009 to June 17, 2012., Results: During generic clopidogrel administration, 1054 PCIs were performed, giving a definite 30-day ST incidence of 0.38% (4 of 1054) among these patients. By comparison, there were 2 episodes of definite 30-day ST during the 80 days immediately preceding generic clopidogrel use (2 of 1114), while 3-year historic data indicated a definite 30-day ST incidence of 0.14% (20 of 14 432), representing a 2.7-fold increase in definite 30-day ST with generic clopidogrel use (P = .076). Exclusion of 3 historic controls with a defined reason for ST (noncompliance, marked thrombocytosis) gave a 3.2-fold increase in 30-day ST with generic clopidogrel (P = .050). An ST-predictive algorithm revealed no difference in the likelihood of ST between patients receiving generic clopidogrel and historic controls., Conclusions: We observed an unexpected >2-fold increase in ST coincident with generic clopidogrel use. Although we cannot ascribe causality, this observation warrants increased vigilance and close monitoring of patients receiving generic clopidogrel.

Background: Phenotypic modulation or switching of vascular smooth muscle cells from a contractile/quiescent to a proliferative/synthetic phenotype plays a key role in vascular proliferative disorders such as atherosclerosis and restenosis. Although several calcium handling proteins that control differentiation of smooth muscle cells have been identified, the role of protein phosphatase inhibitor 1 (I-1) in the acquisition or maintenance of the contractile phenotype modulation remains unknown., Methods and Results: In human coronary arteries, I-1 and sarco/endoplasmic reticulum Ca2+ -ATPase expression is specific to contractile vascular smooth muscle cells. In synthetic cultured human coronary artery smooth muscle cells, protein phosphatase inhibitor 1 (I-1 target) is highly expressed, leading to a decrease in phospholamban phosphorylation, sarco/endoplasmic reticulum Ca2+ -ATPase, and cAMP-responsive element binding activity. I-1 knockout mice lack phospholamban phosphorylation and exhibit vascular smooth muscle cell arrest in the synthetic state with excessive neointimal proliferation after carotid injury, as well as significant modifications of contractile properties and relaxant response to acetylcholine of femoral artery in vivo. Constitutively active I-1 gene transfer decreased neointimal formation in an angioplasty rat model by preventing vascular smooth muscle cell contractile to synthetic phenotype change., Conclusions: I-1 and sarco/endoplasmic reticulum Ca2+ -ATPase synergistically induce the vascular smooth muscle cell contractile phenotype. Gene transfer of constitutively active I-1 is a promising therapeutic strategy for preventing vascular proliferative disorders.

Aims: Emerging data have indicated unexpected complexity in the regulation of vascular and bone calcification. In particular, several recent studies have challenged the concept of a universally positive relationship between body morphology [weight, height, body mass index (BMI), body surface area (BSA)] and the extent of vascular calcification. We sought to clarify these discrepancies and investigated the relationship between index lesion coronary artery calcification (CAC) and body morphology in patients undergoing percutaneous coronary intervention (PCI) using three-dimensional intravascular ultrasound (IVUS)., Methods and Results: We analysed CAC in patients who underwent PCI with pre-intervention IVUS imaging. The main outcome measure was the calcium index (CalcIndex); a three-dimensional IVUS-derived measure of total calcification per obstructive coronary lesion. A total of 346 patients (65.3 ± 10.6 years; 29.5% females) underwent PCI with IVUS-based CAC assessment. CalcIndex was categorized as zero-low (0-0.1399; n = 152) or intermediate-high (0.1400-1.2541; n = 194). All measures of body morphology were lower in patients with intermediate-high CalcIndex (height, P = 0.024; weight, P = 0.008; BMI, P = 0.064; BSA, P = 0.005). In adjusted multivariable models, weight and BSA were independent inverse predictors of intermediate-high CalcIndex [weight: odds ratio (OR) 0.986, P = 0.017; BSA: OR 0.323, P = 0.012] while CalcIndex also trended towards an inverse association with both height (P = 0.068) and BMI (P = 0.064). These independent inverse associations were consistent across multiple clinical subgroups, including stratification by age, race, gender, diabetes, and renal impairment., Conclusion: Using three-dimensional IVUS to assess vascular calcification, these data confirm an independent, inverse relationship between body size and index lesion CAC in patients with obstructive coronary artery disease.

Pluripotent stem cells (PSCs) represent an appealing source from which to develop cell replacement therapies. Different initiatives have been launched to promote their development toward clinical applications. This article will review the main questions that should be considered before translating PSC-derived cardiomyocytes into clinical investigations, including the development of good manufacturing practice-level PSC lines, the development of efficient protocols to generate pure populations of cardiac myocytes, and the development of techniques to improve the retention and survival rate of transplanted cells.

Objective: To determine the impact of suture-mediated vascular closure devices (VCDs) on net adverse clinical events (NACEs) after balloon aortic valvuloplasty (BAV)., Background: Ischemic and bleeding complications are common following transfemoral BAV; however, previous studies have been single center and limited by varying definitions of major bleeding., Methods: The Effect of Bivalirudin on Aortic Valve Intervention Outcomes (BRAVOs) study was a retrospective observational study conducted at two high-volume academic centers over a 6-year period designed to compare the effect of bivalirudin versus unfractionated heparin. This is a subanalysis of 428 consecutive patients who underwent BAV (with 10-13 French sheaths) to compare the effect of hemostasis with VCDs versus manual compression utilizing standardized definitions. NACE was defined as the composite of major bleeding and major adverse clinical events (MACEs). All events were adjudicated by an independent clinical events committee who were blinded to antithrombin use., Results: Preclosure was performed in 269 (62.8%) of patients. While bivalirudin was used more frequently in those with pre-closure (60.6% vs. 37.7%, P < 0.001), a history of prior BAV (11.1% vs. 3.6%, P = 0.04) and peripheral vascular disease (30.7% vs. 19.7%, P = 0.01) was more common in those not undergoing preclosure (n = 159, 37%). Other clinical and demographic features were well balanced between groups. Vascular closure was associated with a significant reduction in NACE (24.5% vs. 10.0% P < 0.001). Results remained significant after adjusting for baseline differences and bivalirudin use (OR 0.38, 95% CI: 0.21-0.68; P = 0.001)., Conclusions: Our study suggests that suture-mediated vascular closure is associated with a substantial reduction in NACE after transfemoral BAV. Large randomized clinical trials should be conducted to confirm our results., (Copyright © 2013 Wiley Periodicals, Inc.)

Objectives: To compare the discriminatory value of differing risk scores for predicting clinical outcomes following PCI in routine practice., Background: Various risk scores predict outcomes after PCI. However, these scores consider markedly different factors, from purely anatomical (SYNTAX risk score [SRS]) to purely clinical (ACEF, modified ACEF [ACEFmod], NCDR), while other scores combine both elements (Clinical SYNTAX score [CSS], NY State Risk Score [NYSRS])., Methods: Patients with triple vessel and/or LM disease with 12 month follow-up were studied from a single center PCI registry. Exclusion criteria included STEMI presentation, prior revascularization and shock. Clinical events at 12 months were compared to baseline risk scores, according to score tertiles and area under receiver-operating-characteristic curves (AUC)., Results: We identified 584 eligible patients (69.8±12.3yrs, 405 males). All scores were predictive of mortality, with the SRS being least predictive (AUC=0.66). The most accurate scores for mortality were the CSS and ACEF (AUC=0.76 for both: P = 0.019 and 0.08 vs. SRS, respectively). For TLR, while the SRS trended toward being positively predictive (P = 0.075), several scores trended towards a negative association, which reached significance for the NCDR (P = 0.045). The SRS and CSS were the only scores predictive of MI (both P < 0.05). No score was particularly accurate for predicting MACE (death+MI+TLR), with AUCs ranging from 0.53 (NCDR) to 0.63 (SRS)., Conclusions: Competing factors influence mortality, MI and TLR after PCI. An increasing burden of comorbidities is associated with mortality, whereas anatomical complexity predicts MI. By combining these outcomes to predict MACE, all scores show reduced utility., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Re-endothelialization is delayed after drug-eluting stent (DES) implantation. In this setting, neointima is more prone to become lipid laden and develop neoatherosclerosis (NA), potentially increasing plaque vulnerability., Methods and Results: Optical coherence tomography and near-infrared spectroscopy with intravascular ultrasound were used to characterize NA in 65 (51 DES and 14 bare-metal stents) consecutive symptomatic patients with in-stent restenosis. Median duration poststent implantation was 33 months. Optical coherence tomography-verified NA was observed in 40 stents with in-stent restenosis (62%), was more prevalent in DES than bare-metal stents (68% versus 36%; P=0.02), and demonstrated significantly higher prevalence of thin-cap neoatheroma (47% versus 7%; P=0.01) in DES. Near-infrared spectroscopy assessment demonstrated that the total lipid core burden index (34 [interquartile range, 12-92] versus 9 [interquartile range, 0-32]; P<0.001) and the density of lipid core burden index (lipid core burden index/4 mm, 144 [interquartile range, 60-285] versus 26 [interquartile range, 0-86]; P<0.001) were higher in DES compared with bare-metal stents. Topographically, NA was classified as I (thin-cap NA), II (thick-cap NA), and III (peri-strut NA). Type I thin-cap neoatheroma was more common in DES (20% versus 3%; P=0.01) and in areas of the stented segment without significant in-stent restenosis (71%). Periprocedural myocardial infarction occurred only in DES (11 versus 0; P=0.05), of which 6 (55%) could be attributed to segments with >70% in-stent restenosis. By logistic regression, prior DES was the only independent predictor of both NA (odds ratio, 7.0; 95% confidence interval, 1.7-27; P=0.006) and periprocedural myocardial infarction (odds ratio, 1.8; 95% confidence interval, 1.1-2.4; P=0.05)., Conclusions: In-stent thin-cap neoatheroma is more prevalent, is distributed more diffusely across the stented segment, and is associated with increased periprocedural myocardial infarction in DES compared with bare-metal stents. These findings support NA as a mechanism for late DES failure.

Objectives: To investigate the use of the GuideLiner "mother-and-child" guide catheter extension system as a simple solution to facilitate initial device delivery in balloon uncrossable chronic total occlusions (CTOs) undergoing percutaneous coronary intervention (PCI)., Background: During PCIs for CTO lesions, an important reason for procedural failure is the inability to deliver a balloon or microcatheter across the lesion., Methods: We retrospectively accessed our interventional registry for 07/01/2010 to 03/21/2012 and extracted data on all CTO lesions involving GuideLiner catheter use. Cine review was performed to identify cases where a guidewire had crossed the CTO and the use of a GuideLiner catheter facilitated initial device delivery., Results: We identified 28 patients that underwent PCI for CTO with a GuideLiner catheter used to assist initial balloon or microcatheter advancement across the culprit lesion. Mean overall CTO length was 26.3 ± 18.1 mm. The GuideLiner catheter was successful in delivering a small balloon to the CTO lesion in 85.7% of cases (24/28). A single CTO PCI resulted in a distal guidewire perforation, but there was no hemodynamic compromise or pericardial effusion and the patient was discharged the next day. Overall procedural success in these selected cases (where a guidewire had already crossed the CTO) was 89.3% (25/28)., Conclusions: The GuideLiner mother-and-child catheter is a simple, safe and efficacious adjunctive device for difficult CTO PCIs where despite standard measures it is not possible to deliver an initial balloon or microcatheter across the occluded segment., (© 2013, Wiley Periodicals, Inc.)

Definitive hematopoiesis emerges during embryogenesis via an endothelial-to-hematopoietic transition. We attempted to induce this process in mouse fibroblasts by screening a panel of factors for hemogenic activity. We identified a combination of four transcription factors, Gata2, Gfi1b, cFos, and Etv6, that efficiently induces endothelial-like precursor cells, with the subsequent appearance of hematopoietic cells. The precursor cells express a human CD34 reporter, Sca1, and Prominin1 within a global endothelial transcription program. Emergent hematopoietic cells possess nascent hematopoietic stem cell gene-expression profiles and cell-surface phenotypes. After transgene silencing and reaggregation culture, the specified cells generate hematopoietic colonies in vitro. Thus, we show that a simple combination of transcription factors is sufficient to induce a complex, dynamic, and multistep developmental program in vitro. These findings provide insights into the specification of definitive hemogenesis and a platform for future development of patient-specific stem and progenitor cells, as well as more-differentiated blood products., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Mice genetically deficient in endothelial nitric oxide synthase (eNOS(-/-)) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. Although the current paradigm holds that this bioactivity derives specifically from the expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed., Approach and Results: To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted wild-type and eNOS(-/-) mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NG-nitroarginine methyl ester and repristinated by the NOS substrate L-arginine and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert (14)C-arginine into (14)C-citrulline in NOS-dependent fashion., Conclusions: These are the first studies to definitively establish a role for a blood-borne eNOS, using cross-transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.

Objectives: This study sought to determine the impact of short-term intensive statin therapy on intracoronary plaque lipid content., Background: Statin therapy significantly reduces the risk for thrombotic events. Whether or not these benefits are attributable to reduction in plaque lipid content remains to be properly documented in human obstructive coronary artery disease (CAD)., Methods: We randomized 87 patients with multivessel CAD undergoing percutaneous coronary intervention and at least 1 other severely obstructive (fractional flow reserve [FFR] ≤0.8) nontarget lesion (NTL) to intensive (rosuvastatin 40 mg daily) or standard-of-care lipid-lowering therapy. NTLs were evaluated at baseline and after 7 weeks of therapy with FFR, near-infrared spectroscopy, and intravascular ultrasound. The primary endpoint was the change in lipid-core burden index at the 4-mm maximal segment (LCBI4mm max), wherever this occurred within the lesion., Results: Upon follow-up, median reduction (95% confidence interval) in LCBI4mm max was significantly greater in the intensive versus standard group (-149.1 [-210.9 to -42.9] vs. 2.4 [-36.1 to 44.7]; p = 0.01). Results remained consistent after adjustment for baseline differences in LCBI between groups and use of change in LCBI across the entire lesion as the dependent outcome., Conclusions: Short-term intensive statin therapy may reduce lipid content in obstructive lesions. These hypothesis-generating findings warrant confirmation in larger studies with longer follow-up. (Reduction in YEllow Plaque by Aggressive Lipid LOWering Therapy [YELLOW]); NCT01567826)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with both chronic kidney disease (CKD) and diabetes mellitus (DM) are at increased risk for thrombotic events compared to those with one abnormality alone. Whether this can be attributed to changes in platelet reactivity among those with both CKD and DM is unknown. We prospectively studied 438 clopidogrel-naïve patients undergoing percutaneous coronary intervention (PCI). Platelet function tests were performed 4-6 hours after loading with 600 mg of clopidogrel. Platelet reactivity was assessed using the VerifyNow system and expressed as P2Y12 reaction units (PRU). High residual platelet reactivity (HRPR) was defined as PRU > 230. Patients were categorised into four groups by the presence or absence of CKD and DM. Among those without CKD or DM (n=166), DM alone (n=150), CKD alone (n=60) and both CKD and DM (n=62) the mean PRU levels were 201.6 ± 96.3, 220.5 ± 101.1, 254.9 ± 106.7 and 275.0 ± 94.5, respectively (p<0.001). Analogously, the prevalence of HRPR was 42.3%, 50.7%, 63.3% and 75.8%, respectively (p< 0.001). Associations between either CKD or DM alone and HRPR were attenuated after multivariable adjustment while the odds for HRPR associated with both CKD and DM remained significant (OR [95% CI]: 2.61 [1.16 - 5.86]). In conclusion, the presence of both CKD and DM confers a synergistic impact on residual platelet reactivity when compared to either condition alone. Whether more potent platelet inhibitors may improve outcomes among patients with both abnormalities warrants investigation.

Objectives: To compare the practical use, safety, and clinical outcomes associated with the TandemHeart (TH) versus Impella Recover 2.5 (IR2.5) devices when used for circulatory support during high-risk percutaneous coronary intervention (PCI)., Background: Small studies and registries suggest safety and efficacy for the TH and IR2.5 percutaneous-left ventricular assist devices (P-LVADs). However, these P-LVADs differ markedly in their insertion, operation, and manner of circulatory augmentation. To date, no study has compared these devices., Methods: We identified 68 patients (49 males, 19 females; age 71.1 ± 12.1 years) from our single-center database that underwent "high-risk" PCI with P-LVAD support from April 2005 to June 2010 (32 with TH, 36 with IR2.5). Relevant data were extracted for analysis., Results: Baseline demographics were similar, including low LVEF (overall mean 31.0 ± 13.7%) and elevated STS mortality risk score (4.2 ± 3.7%). Angiographic characteristics were also similar, with a mean of 2.4 ± 1.0 lesions treated per patient, and 29% undergoing left main PCI. PCI success rates were 99% in both groups, with similar in-hospital outcomes and a combined 7% major vascular access site complication rate. A single episode of left atrial perforation occurred during TH use. No patient required emergent CABG and no in-hospital deaths occurred. The 30-day MACE rate (death, myocardial infarction, target lesion revascularization) was 5.8%. There were no differences between the IR2.5 and TH groups with respect to short- or long-term clinical outcomes., Conclusions: The IR2.5 and TH assist devices are safe, equally effective, and associated with acceptable short- and long-term clinical outcomes in patients undergoing "high-risk" PCI., (Copyright © 2013 Wiley Periodicals, Inc.)

Patients with ST-segment elevation myocardial infarction (STEMI) admitted during nonregular working hours (off-hours) have been reported to have greater mortality than those admitted during regular working hours (on-hours), perhaps because of the lower availability of catheterization laboratory services and longer door-to-balloon times. This might not be the case, however, for hospital centers in which primary percutaneous coronary intervention (PCI) is invariably performed. We conducted a substudy using the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction study data to determine whether the STEMI arrival time was associated with differing clinical outcomes. We identified all patients with STEMI admitted to a PCI-capable hospital who underwent primary PCI. Patients presenting during on-hours were compared to those presenting during off-hours. The primary outcome of death, major adverse cardiovascular events, and net adverse clinical events was examined. We identified 2,440 patients (1,205 [49%] on-hours and 1,235 [51%] off-hours). Similar baseline characteristics were observed. The off-hour patients had a significantly longer door-to-balloon time (92 vs 75 minutes; p <0.0001) and total ischemic time (209 vs 194 minutes; p <0.0001). Despite these differences, the risk-adjusted all-cause mortality, major adverse cardiovascular events, and net adverse clinical events rates were similar for both groups during the in-hospital, 1-year, and 3-year follow-up. In conclusion, patients with STEMI presenting to primary PCI hospitals during off-hours might have slightly longer delays to revascularization; however, they experienced similar short- and long-term survival and clinical outcomes as those arriving during on-hours., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The involvement of vascular factors in Alzheimer dementia was first appreciated over 100 years ago. Recently, significant advances in our understanding of these brain-vascular relationships have taken place. Vascular cognitive impairment is now recognized as a distinct group of interrelated vascular-based neurological insults that can accumulate and lead to dementia. Importantly, the pathology of vascular cognitive impairment extends far beyond brain destruction wrought by major stroke. Other subtle changes may also arise that contribute to vascular cognitive impairment and dementia, including subclinical stroke, white-matter changes such as hyperintensities and lipohyalinosis, small lacunar infarcts, cerebral hypoperfusion, and compromise of the blood-brain barrier. In this review we critically examine the emerging body of evidence that relates atherosclerotic risk factors, brain functioning, and Alzheimer disease., (© 2012 Mount Sinai School of Medicine.)

Percutaneous left ventricular assist devices (P-LVADs) can be life saving and may permit the stabilization of a patient in cardiovascular collapse who would otherwise face imminent demise. For specific patients and clinical indications, or where a greater degree of hemodynamic support is required, numerous studies have demonstrated the feasibility and safety of the newer generation P-LVADs. The potential applications for P-LVADs have continued to expand, now including diverse uses such as support for cardiogenic shock, bridge to and following cardiac surgery, and more novel applications such as complex electrophysiologic mapping and ablation studies of unstable ventricular rhythms., (Copyright © 2012 Elsevier Inc. All rights reserved.)