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In the period 1935–1939, following the death of head of state Marshal Piłsudski, the Polish national government adopted a more authoritarian and nationalist stance. Piłsudski had been considered by some Polish Jews as a protector of national and religious minorities. After his death in May 1935, institutional antisemitism experienced a dramatic increase. In the public sphere, certain newspapers regularly featured antisemitic “news reports,” opinion pieces and cartoons of an extreme nature. The newspaper ABC, for instance, advocated boycotts of Jewish businesses and shops, listing them by name, and encouraged Jewish emigration. In universities, the increasing discrimination against Jews has been well documented. MostPolish universities instituted restrictions on the number of Jewish students they would admit, or else barred them altogether. The education ministry willingly turned a blind eye to the admission policies of the university authorities. At the beginning of the academic year 1938–1939, for example, only three students in the first year of medical studies in Lwów (less than 1% of the new intake) were Jews, and none in Kraków. After discussing antisemitism in newspapers and universities in the late 1930s, this article will examine documents held in the State Archive of Ivano-Frankivsk Oblast (DAIFO) concerning relations between the Jewish communities in the Stanisławów region, and the district, provincial and national authorities, including the national Ministry for Religious Denominations and Public Enlightenment. Much of this documentation concerns the town of Dolina. With the backing of the district authorities, an attempt was made to install as assistant rabbi in the town a certain Ksyel Juda Halberstam. This move was strongly opposed by many members of the Dolina Jewish community, as well as by its senior rabbi. The correspondence sheds light on the protracted struggle between the different parties until the assistant rabbi was finally installed in late 1938. These files on the Dolina episode highlight the desire on the part of the authorities to control the rabbis, and through them the members of their communities. Information was systematically gathered on all the rabbis in the province, with particular emphasis on their moral behaviour, their perceived loyalty to the state, and their fluency in the Polish language. These actions, in turn, reflect an underlying suspicion over the extent of the rabbis’ “Polishness” and a fear, in an era of growing nationalism, of “antinational” behaviour. Such suspicions of loyalty were particularly marked where rabbis were thought to have Zionist links.

Controlled trials provide the most valid determination of the efficacy and safety of an intervention, but large cardiovascular clinical trials have become extremely costly and complex, making it difficult to study many important clinical questions. A critical question, and the main objective of this review, is how trials might be simplified while maintaining randomisation to preserve scientific integrity and unbiased efficacy assessments. Experience with alternative approaches is accumulating, specifically with registry-based randomised controlled trials that make use of data already collected. This approach addresses bias concerns while still capitalising on the benefits and efficiencies of a registry. Several completed or ongoing trials illustrate the feasibility of using registry-based controlled trials to answer important questions relevant to daily clinical practice. Randomised trials within healthcare organisation databases may also represent streamlined solutions for some types of investigations, although data quality (endpoint assessment) is likely to be a greater concern in those settings. These approaches are not without challenges, and issues pertaining to informed consent, blinding, data quality and regulatory standards remain to be fully explored. Collaboration among stakeholders is necessary to achieve standards for data management and analysis, to validate large data sources for use in randomised trials, and to re-evaluate ethical standards to encourage research while also ensuring that patients are protected. The rapidly evolving efforts to streamline cardiovascular clinical trials have the potential to lead to major advances in promoting better care and outcomes for patients with cardiovascular disease.

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g., all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.

Electronic health records (EHRs) provide opportunities to enhance patient care, embed performance measures in clinical practice, and facilitate clinical research. Concerns have been raised about the increasing recruitment challenges in trials, burdensome and obtrusive data collection, and uncertain generalizability of the results. Leveraging electronic health records to counterbalance these trends is an area of intense interest. The initial applications of electronic health records, as the primary data source is envisioned for observational studies, embedded pragmatic or post-marketing registry-based randomized studies, or comparative effectiveness studies. Advancing this approach to randomized clinical trials, electronic health records may potentially be used to assess study feasibility, to facilitate patient recruitment, and streamline data collection at baseline and follow-up. Ensuring data security and privacy, overcoming the challenges associated with linking diverse systems and maintaining infrastructure for repeat use of high quality data, are some of the challenges associated with using electronic health records in clinical research. Collaboration between academia, industry, regulatory bodies, policy makers, patients, and electronic health record vendors is critical for the greater use of electronic health records in clinical research. This manuscript identifies the key steps required to advance the role of electronic health records in cardiovascular clinical research.

An abdominal aortic aneurysm (AAA) is a common aortic wall disease with an increased prevalence in the elderly population (4-8% for those aged65 years). Many AAAs are slow growing and remain insidious. Current standard of care for patients with small AAAs (49 mm) is surveillance, with interventional therapy (open surgical repair or endovascular aneurysm repair) recommended for large (50-55 mm), rapidly growing (10 mm/year) or symptomatic AAAs. Although open surgical repair or endovascular aneurysm repair are effective, significant short- and long-term postoperative morbidity and mortality occurs. Currently, there is no pharmacological treatment specific for AAA; the need for the development of targeted pharmacological therapies based on clinically relevant and feasible outcomes acceptable to the medical community, regulatory agencies and third-party payers is high. A consensus on such end points will be critical to accelerating the development of pharmacological agents to prevent formation, arrest the expansion and reduce the rupture risk of AAA.

Background Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates. Design The CANTOS will evaluate whether interleukin-1β (IL-1β) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1β, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1β driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation. Summary If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

Randomized clinical trials (RCTs) are the gold standard for building evidence. However, the strength of evidence in cardiovascular disease guidelines is not keeping pace with the number of emerging recommendations,1 perhaps reflecting the growing difficulties in developing adequately powered RCTs. In the context of secondary prevention after acute coronary syndromes (ACS), the increase in sample size needed to establish benefit, the rising costs, and the growing complexity of the regulatory environment and study logistics are challenging the development of new therapies. In response to these concerns, the European Society of Cardiology (ESC) convened an ad hoc meeting in May 2009. This paper summarizes the discussions and offers suggestions for improvement ( Table 1 ), which may complement previous proposals.2 [Note: the ideas presented are those of the individual participants (listed in the Appendix) and do not reflect the ideas of the participating bodies]. View this table: Table 1 Strategies to improve research on secondary prevention after acute coronary syndromes In spite of major advances, our understanding of the pathophysiology of coronary atherosclerosis progression and triggers of recurrent thrombotic events after ACS remains limited. To enhance therapeutic development, a clearer picture of coronary atherothrombosis is required. For that, large collaborative consortia between Pharma and acadaemia focused on pathophysiology, genetic epidemiology, new biomarkers, and other intermediate measurements, as well as clinical research on traditional outcomes are needed to better understand the natural history of coronary artery disease. The identification of new pathways and therapeutic targets, as well as the genetic, phenotypic, or behavioural causes underlying the wide individual variations in responses to therapies, particularly antithrombotic treatments should be prioritized. Traditional and new ways of research will be essential to achieve these objectives ( Table 1 ).3 Better ways are also needed to identify patients at high risk for coronary or other vascular recurrences as well as the …

Objectives The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Background Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Methods Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (ΔSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Results Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (ΔSI 0.13; p = 0.0003) and at 12 weeks (ΔSI 0.20; p Conclusions Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to “anti-inflammatory” interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589 )

Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.

Background— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results— This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA 2 inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. Background therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88±34 mg/dL; darapladib, 84±31 mg/dL; P =0.37). In contrast, Lp-PLA 2 activity was inhibited by 59% with darapladib ( P P =0.22) or plasma high-sensitivity C-reactive protein ( P =0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5±17.9 mm 3 ; P =0.009), whereas darapladib halted this increase (−0.5±13.9 mm 3 ; P =0.71), resulting in a significant treatment difference of −5.2 mm 3 ( P =0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume ( P =0.95). Conclusions— Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA 2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA 2 inhibition may represent a novel therapeutic approach.

Objectives This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, on biomarkers of cardiovascular (CV) risk. Background Elevated Lp-PLA2 levels are associated with an increased risk of CV events. Methods Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA2 activity and other biomarkers. Results Baseline low-density lipoprotein cholesterol (LDL-C) was 67 ± 22 mg/dl. Plasma Lp-PLA2 was higher in older patients (≥75 years), in men, in those taking atorvastatin 20 mg, at LDL-C ≥70 mg/dl or high-density lipoprotein cholesterol (HDL-C) Conclusions Darapladib produced sustained inhibition of plasma Lp-PLA2 activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA2 inhibition is associated with favorable effects on CV events. (SB-480848 in Subjects With Coronary Heart Disease; NCT00269048)

Background Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. Methods APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitozone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. Result A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body 2 mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. Conclusions APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitozone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease. (Am Heart J 2008; 156:1074-9.)

Background Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is an emerging cardiovascular risk marker. To explore the biologic role of Lp-PLA 2 in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions. Methods and results Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA 2 activity was observed at 1 month. This was accompanied by upregulated Lp-PLA 2 mRNA expression by peripheral blood mononuclear cells (PBMC) at 3 months, and elevated Lp-PLA 2 mRNA expression in coronary arteries at 6 months. These changes were paralleled by increased inflammatory responses by circulating PBMC (ICAM-1, IL-6), in coronary tissues (ICAM-1, VCAM-1), and the subsequent accumulation of inflammatory cells. In human PBMC, proinflammatory mediators augmented the synthesis and release of functional Lp-PLA 2 . Furthermore, lysophosphatidylcholine (lysoPC), a product of Lp-PLA 2 activity, induced an increase in several inflammatory cytokines (IL-1β, IL-6, TNF-α) in a concentration-dependent manner. In contrast, Lp-PLA 2 inhibition (SB677116; 1 μM) abrogated the inflammatory response elicited by oxidized LDL. Conclusions In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA 2 expression. In vitro, Lp-PLA 2 activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA 2 inhibition abolished inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA 2 .

Aims Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines.Methods and results The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development.Conclusions A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

Objectives Our purpose was to assess noninvasive imaging in detection of subclinical atherosclerosis and to examine novel invasive modalities to describe prevalence and temporal changes in putative characteristics of “high-risk” plaques. Background Conventional coronary imaging cannot identify “high-risk” lesions. Methods Conventional (quantitative angiography and intravascular ultrasound [IVUS]) and novel imaging (IVUS-based palpography and gray scale echogenicity) were performed at baseline and 6 months later in 67 patients with diverse clinical presentations. Different imaging techniques were compared within a common segment defined by multislice computed tomography (MSCT). Results Compared with IVUS, the sensitivity, specificity, and positive and negative predictive value of MSCT for detecting significant plaque was 86%, 69%, 90%, and 61%, respectively. In coronary arteries with Conclusions Mild angiographic disease is associated with large atherosclerotic plaques on MSCT. Conventional invasive coronary imaging reveals static luminal and plaque dimensions on standard medical therapy with plaque hypoechogenicity remaining unchanged over the 6-month period. By contrast, palpography measurements of strain correlate with clinical presentation and significantly decrease on standard medical therapy. Novel imaging modalities, such as palpography, might provide insights into plaque biology and might eventually serve as intermediate end points in interventional trials.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that is produced by inflammatory cells, is bound to circulating LDL, and is involved in hydrolyzing polar phospholipids, including those found in oxidized low-density lipoproteins. To date, the biological role of Lp-PLA(2) in atherogenesis has been controversial, with initial reports purporting an atheroprotective effect attributable to the degradation of platelet activating factor and similar molecules. However, more recent studies suggest a proatherogenic role for this enzyme, which is attributed to Lp-PLA(2)-mediated hydrolysis of oxidatively modified low-density lipoproteins that results in the accumulation of proinflammatory products. The liberation of lysophosphatidylcholine and oxidized nonesterified fatty acids from oxidized phospholipids by the action of Lp-PLA(2) results in diverse inflammatory effects on various cell types involved in atherogenesis. This concept is further supported by a number of recently published epidemiology studies suggesting that plasma levels of the enzyme predict future cardiovascular events independent of conventional risk factors. The development of selective inhibitors of Lp-PLA(2) that inhibit enzyme activity in the circulation as well as within human atherosclerotic lesions opens the possibility of therapeutic manipulation of vascular inflammatory processes to reduce residual cardiovascular events in high risk individuals who continue to suffer fatal and nonfatal events despite the current standard of care.

Although the clinical benefit of statins is well established, these agents reduce the risk of cardiovascular events by only 20 - 40%, and the residual risk for high-risk patients is considerable. The recognition of atherosclerosis as an inflammatory disease has opened the door to numerous complementary therapeutic approaches to further reduce risk and the overall burden of cardiovascular disease. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammatory marker of cardiovascular risk that is being evaluated as a potential therapeutic target. The biological function of this enzyme in atherosclerosis has been controversial but recent evidence supports its pro-atherogenic role. The enzyme is predominantly bound to low-density lipoprotein cholesterol particles in humans, and its activity produces bioactive lipid mediators that promote inflammatory processes present at every stage of atherogenesis, from atheroma initiation to plaque destabilisation and rupture. Initial clinical studies suggest that the inhibitors of Lp-PLA(2) can block enzyme activity in plasma and within atherosclerotic plaques. However, more studies are needed to determine the potential clinical benefits of inhibiting Lp-PLA(2).

The formation of vascular lesions is invariably associated with the accumulation of mesenchymal cells and their products in the intima, which either compromise the vessel lumen or contribute to retention of atherogenic molecules (reviewed in References 1 and 2).1,2⇓ As a result, pathological intimal hyperplasia is pivotal in the development of a wide range of clinical conditions, which are associated with increased cardiovascular morbidity and mortality. Nonetheless, the origin of intimal cells has remained a controversial issue in vascular biology and clinical cardiology. In addition to the expansion of preexisting intimal cells, the initial hypothesis argued for phenotypic modulation of medial smooth muscle cells (SMCs) from a contractile to a synthetic phenotype (dedifferentiation), resulting in their migration into the intima.3,4⇓ Several recent investigations, however, have shed new light on the mechanisms of arterial remodeling, coronary restenosis after transcatheter interventions, and vein graft changes after arterialization, which are accompanied by marked alterations in cellular composition of the affected vessel. Understanding how the vasculature alters its composition holds the key to discerning vascular responses under physiological and pathological conditions (Figure 1). In a recent issue of Circulation Research , Hu and colleagues5 join this quest, focusing on the origin of intimal cells during vein graft remodeling. In contrast to numerous observations after arterial injury, there are relatively few studies of vein graft remodeling under dyslipidemic conditions, making the analysis of vein grafts in apoE-deficient mice clearly relevant. In different types of transgenic animals, the authors demonstrated that intima of venous isografts appeared to contain SMC-like cells originating from both donor and recipient, with no apparent contribution of bone marrow-derived cells. These findings suggest vascular-bed dependent differences in the mechanisms of repair and remodeling. They also underscore the diverse cellular origin of intimal hyperplasia, which may originate from …

Abstract —Reactive oxygen species (ROS), produced by cellular constituents of the arterial wall, provide a signaling mechanism involved in vascular remodeling. Because adventitial fibroblasts are actively involved in coronary remodeling, we examined whether the changes in the redox state affect their phenotypic characteristics. To this end, superoxide anion production and NAD(P)H oxidase activity were measured in porcine coronary arteries in vivo, and the effect of ROS generation on adventitial fibroblast proliferation was examined in vitro. Superoxide production (SOD- and Tiron-inhibitable nitro blue tetrazolium [NBT] reduction) increased significantly within 24 hours after balloon-induced injury, with the product of NBT reduction present predominantly in adventitial fibroblasts. These changes were NAD(P)H oxidase–dependent, because diphenyleneiodonium (DPI) abolished superoxide generation ( P phox and p67 phox in adventitial fibroblasts (immunohistochemistry). Serum stimulation of isolated adventitial fibroblasts produced time-dependent increases in ROS production (peak 3 to 6 hours). The inhibition of ROS generation with NAD(P)H oxidase inhibitor (DPI) or the removal of ROS with antioxidants (Tiron, catalase) abrogated proliferation of adventitial fibroblasts. These results indicate that vascular NAD(P)H oxidase plays a central role in the upregulation of oxidative stress after coronary injury, providing pivotal growth signals for coronary fibroblasts.

Background —Recent findings suggesting the involvement of adventitial cells in coronary repair have raised questions regarding the phenotypic “plasticity” of medial smooth muscle cells (SMCs). Accordingly, the aims of the present study were to examine the characteristics of coronary medial and adventitial cells and to compare the responses of coronary and noncoronary SMCs to stimulation. Methods and Results —Enzymatically isolated coronary SMCs (human and porcine) were distinct from noncoronary SMCs, showing poor adhesion and spreading, as well as lower proliferation, collagen synthesis, and LDL degradation. Several extracellular matrix components (Matrigel, collagen I and IV, laminin, vitronectin, fibronectin) or growth factors (epidermal growth factor, platelet-derived growth factor-BB, insulin growth factor-1, interleukin-1α) failed to augment the adhesion or proliferation of coronary SMCs to the levels observed in noncoronary SMCs. Unlike coronary SMCs, coronary fibroblasts demonstrated high adhesion, proliferation, collagen synthesis, and avid LDL metabolism. Limited responses of coronary SMCs were associated with sustained expression of differentiation markers (α-smooth muscle actin, h-caldesmon, and smooth muscle myosin heavy chain), whereas noncoronary SMCs showed marked phenotypic heterogeneity. Conclusions —Coronary SMCs appeared to maintain highly differentiated phenotype in response to stimulation, whereas coronary adventitial fibroblasts demonstrated several characteristics that are essential during vascular repair. Coronary SMCs, however, were distinct from noncoronary medial cells, which displayed greater phenotypic heterogeneity and versatility in culture. We postulate that the mechanism of vascular repair may differ among vascular beds, pointing to the importance of coronary artery–specific investigations in vascular biology.

Abstract —The migration of vascular cells is regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Because the activation of adventitial fibroblasts has been implicated in coronary repair, we have examined regional differences in cell outgrowth and the synthesis of MMPs/TIMPs in different layers of porcine coronary arteries. Coronary medial explants demonstrated significantly slower cell outgrowth than coronary adventitia in culture ( P P P P

There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

Background: Myofibroblasts are a prominent cell type in wound healing. The goal of this study was to examine the extent to which myofibroblasts contribute to structural changes in saphenous vein bypass grafts. Methods and results: Control veins and reversed saphenous vein bypass conduits of porcine carotid arteries were examined 2 to 4, 7 to 14, and 30 to 90 days after surgery with immunohistochemical markers of cellular proliferation (proliferating cell nuclear antigen), cytoskeletal protein production (α–smooth muscle actin and desmin), and histochemistry (Verhoeff's stain). Control veins demonstrated an extremely low level of cellular proliferation and no evidence of myofibroblasts in the adventitia, media, or intima. After bypass grafting, cellular proliferation was followed by myofibroblast formation, which occurred in the perivascular area and within the media. This was evidenced by a dense, but transient, expression of α–smooth muscle actin and a variable expression of desmin at 1 to 2 weeks, and with a significant increase in collagenous tissue by 1 to 3 months. Major cytoskeletal protein changes also occurred in the intima, with the appearence of α–smooth muscle actin positive cells at 7 to 14 days. α–Smooth muscle actin was still present in the neointima at 1 to 3 months, which is compatible with a persistent myofibroblast formation. Conclusion: Myofibroblast formation occurs around and within saphenous veins after bypass grafting. This phenomenon is associated with significant remodeling of the vein grafts. The histologic changes are strikingly similar to events that occur during wound healing and may have implications for the development of neointimal hyperplasia and late vein graft disease(J Thorac Cardiovasc Surg 1997;114:38-45)

Background Aortocoronary saphenous vein grafts (SVGs) undergo structural changes that render them susceptible to atherosclerosis. Accordingly, the origin of neointimal hyperplasia was examined in porcine arterialized SVGs to determine the mechanism of vein graft remodeling. Methods and Results At 2 to 4 days after surgery, the percentage of cells lacking differentiation markers characteristic for smooth muscle (SM) cells (ie, α-SM actin, desmin, and SM myosin) increased within the media of SVGs interposed in the carotid arteries ( P Conclusions Perivascular fibroblasts may infiltrate injured media of arterialized SVGs, differentiate to myofibroblasts (acquiring α-SM actin), and contribute to vein graft remodeling. The similarities between porcine and human SVGs regarding the repertoire of cytoskeletal proteins suggest the involvement of myofibroblasts in graft remodeling in the clinical setting.

Background Coronary injury triggers differentiation of activated adventitial fibroblasts to myofibroblasts, which may contribute to neointimal formation and vascular remodeling. Accordingly, the purpose of this study was to examine the cellular origin of the enhanced synthesis of extracellular matrix proteins during coronary repair. Methods and Results The time course and localization of collagen and elastin expression were examined by in situ hybridization and immunohistochemistry in porcine coronary arteries after balloon-induced injury. Procollagen-α 1 (I) transcripts and intracellular type I procollagen protein increased in the adventitia within 2 days after injury. This was followed by a sustained synthesis of type I procollagen in neointima beginning at 7 days and the extracellular accumulation of type I collagen in both layers. The origin of synthetic cells was further examined by colocalization of type I procollagen and bromodeoxyuridine labeling to activated adventitial cells, which translocated to neointima. Neointimal cells exhibited sustained synthetic activity manifested by the presence of type I procollagen and elastin at 3 months after injury. In contrast, the media showed only minor changes in the synthesis of collagen or elastin throughout coronary repair. Conclusions Activated adventitial fibroblasts are endowed with synthetic capabilities after coronary injury. They express type I procollagen, with some of them translocating to the intima, where they continue to synthesize procollagen. The accumulation of type I collagen is evident in the adventitia and neointima, whereas elastin accumulates mainly in neointima. These findings support the involvement of adventitial fibroblasts in coronary repair and remodeling after endoluminal injury.

We evaluated the effect of (dual) renin-angiotensin-aldosterone system (RAAS) blockade with valsartan and an ACE inhibitor [92.7% of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial (Val-HeFT)] in patients with NYHA class II-IV heart failure (HF) and reduced EF on cardiovascular (CV) death and HF hospitalization by subgroups and by presence of early worsening of renal function (EWRF) and according to baseline estimated glomerular filtration rate (eGFR).We analysed the data from 5010 patients enrolled in the Val-HeFT study. A total of 2346 (46.8%) patients had baseline renal impairment (i.e. baseline eGFR60 mL/min/1.73 m(2)). Further, 425 patients (8.6%) had EWRF (i.e. eGFR decrease20% within 1 month after randomization), whereas 4503 patients (91.4%) had ≤20% decline in eGFR. Overall, the difference between valsartan and placebo on the composite endpoint of CV death and HF hospitalization was significant [P = 0.0005; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.75-0.92)]. In patients with baseline renal impairment, the difference between the treatment groups was also significant (P = 0.0002; HR 0.76, 95% CI 0.66-0.88). Patients with EWRF had higher risk of CV death and HF hospitalization vs. those without ERWF (P0.0001; HR 1.44, 95% CI 1.21-1.71), and within the EWRF group a significant difference was also observed between valsartan and placebo (P = 0.0086; HR 0.63, 95% CI 0.45-0.89). However, the interaction between treatment and eGFR at Month 1 was not significant (P = 0.1160).Benefits were maintained in patients with renal dysfunction at baseline and those who experienced EWRF.

Peripheral vascular complications are a significant source of morbidity after coronary artery stent implantation. The goal of this study was to assess the incidence, risk factors, and management of vascular complications after stent placement. The study population consisted of 101 consecutive patients who underwent stent placement for either elective or bailout indications. All patients received a standardized anticoagulation regimen of aspirin, dipyridamole, low molecular weight dextran, heparin, and warfarin. Peripheral vascular access sites were examined daily until hospital discharge. Vascular complications occurred in 16 of 101 (16%) patients, including femoral artery pseudoaneurysm (n = 11), hematoma requiring transfusion or surgery (n = 4), and arterlovenous fistula (n = 1). Intervention was required in 14 of 16 (88%) patients with complications. These included transfusion (n = 7), ultrasound-guided compression (n = 8), and/or vascular surgery (n = 7). Length of hospital stay was prolonged in patients with complications (14 ± 9 vs. 8 ± 5 d, P < 0.001). The development of peripheral vascular complications did not correlate with clinical or procedural variables such as age, cardiovascular risk factors, arterial sheath size, or elective vs. bailout indication. After the introduction of a pneumatic vascular compression device (FemoStop, C.A. Bard, Billerica, MA), a significant reduction In vascular complications was observed. Complications occurred in only 1 of 41 (2.4%) patients in whom the compression device was used in contrast to 13 of 58 (22.4%) patients compressed manually (P < 0.01). Thus peripheral vascular complications are frequent after coronary artery stent placement and are associated with serious morbidity and prolongation of hospital stay. These complications are significantly reduced by the use of a pneumatic vascular compression device despite intensive systemic anticoagulation. © 1996 Wiley-Liss, Inc.

A new class of vasodilators exhibiting selective dopamine-1 receptor agonist activity is being introduced into clinical practice. Inasmuch as various vasodilators either augment or decrease myocardial blood flow ("coronary steal") depending on their pharmacologic action, the goal of this study was to assess the effects of fenoldopam (selective dopamine-1 receptor agonist) and dopamine (nonselective dopamine-1 receptor agonist) on regional myocardial blood flow in the presence of coronary occlusion. Accordingly, in 16 dogs anesthetized with pentobarbital, the left anterior descending coronary artery was occluded. Cardiovascular and renal hemodynamic effects were measured before and after intravenous infusion of renal equipotent doses of either fenoldopam (n = 9, 0.1 micrograms/kg/min) or dopamine (n = 7, 1 micrograms/kg/min). Both fenoldopam and dopamine caused a significant and comparable increase in renal blood flow. Fenoldopam but not dopamine significantly decreased the calculated peripheral vascular resistance and subsequently increased cardiac output. Dopamine had no effect on regional myocardial blood flow. In contrast, fenoldopam augmented transmural myocardial blood flow in normal (from 114 +/- 10 to 188 +/- 27 ml/100 gm/min, p less than 0.02) and ischemic border myocardium (from 45 +/- 5 to 68 +/- 11 ml/100 gm/min, p less than 0.03 and p less than 0.02 vs dopamine). There was a significant increase in blood flow to both the endocardial and epicardial layers of normal and ischemic border myocardium. These changes were accompanied by a significant reduction in coronary vascular resistance in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

The composition of atherosclerotic coronary plaque is a major determinant of future clinical events. Spectral analysis of IVUS radiofrequency data has demonstrated potential to provide detailed quantitative information on plaque composition. We prospectively assessed plaque composition in matched coronary segments at a six-month interval and sought to explore correlations between temporal changes in plaque composition and circulating biomarkers.Twenty coronary segments (mean baseline length, 29.9+/-14.1mm) with non-significant angiographic (50 % diameter) stenosis, in non-culprit vessels of patients (n=20) referred for percutaneous intervention, were studied at baseline and six-month follow-up. Spectral analysis of IVUS radiofrequency data, obtained with a 30 MHz catheter in segments matched on predefined anatomic landmarks, was performed with IVUS-Virtual Histology software. After 6 months, an overall decrease in the level of different biomarkers of instability was present. There were no significant changes in absolute values (mm2) of plaque components; calcium (0.036+/-0.05 vs. 0.033+/-0.04), fibrous (2.68+/-1.5 vs. 2.90+/-1.5), fibrolipidic (0.77+/-0.4 vs. 0.73+/-0.4), and lipid core (0.42+/-0.4 vs. 0.52+/-0.5), between baseline and six-months. Nor did any conventional IVUS variable (lumen, vessel, or plaque cross-sectional area, or percent area stenosis). Change in lipid core area (r=0.51, p=0.024), fibrous area (r=0.49, p=0.033) and calcium area (r=0.63, p=0.004), were significantly correlated with change in Lp-PLA2 activity.Routine medical care does not result in significant overall changes in IVUS-derived plaque size or composition over a 6-month period. This study provides indication of quantifiable boundaries beyond which modifications in tissue composition might be interpreted as statistically significant.

Objectives IBIS-1 was a pilot study undertaken to correlate coronary imaging with circulating biomarker expression in patients with stable angina, unstable angina and acute myocardial infarction. We hypothesized that patients at high risk of future events could be identified in the future by a combination of high risk plaque features by plaque echogenicity and palpography and a set of circulating blood biomarkers. Results and methods We assessed the expression of conventional biomarkers and novel marker protein microarray (170 analytes) over 6months. There were no strong correlations observed between conventional biomarkers and coronary imaging in non-culprit artery. Proteomic microarray was performed in 66 patients. Seventy eight (45%) analytes showed dynamic changes over time. Using hierarchical clustering and principal component analysis two subsets of biomarkers were identified: initial up-regulation and decrease over time (D-dimer, hepatocyte growth factor, CXCL9/MIG, platelet factor 4/CXCL4, CTACK, C-6 Kine, follistatin, and FGF-7) and the opposite increase (PAI-1- anti-apoptotic protein and I-309 — chemokine induced on the human endothelium by Lp(a)). Conclusions Proteomic analysis identifies dynamic patterns in circulating biomarkers in a wide range of patients with coronary artery disease. Further large natural history studies are needed to better define multibiomarker sets for identification of patients at risk of future CV events.

BACKGROUND The goal of this study was to evaluate the role of the fibrinolytic system in patients with unstable angina at rest associated with transient electrocardiographic changes. METHODS AND RESULTS Tissue plasminogen activator activity in plasma was comparable among patients with unstable angina (n = 17), patients with stable exertional angina (n = 10), and control patients with normal coronary arteriograms (n = 8). In contrast, plasminogen activator inhibitor-1 (PAI-1) activity in plasma was elevated in the unstable angina group (21.67 +/- 9.52 AU/ml) as compared with either the stable angina group (12.01 +/- 7.06 AU/ml, p less than 0.02) or the controls (12.49 +/- 8.54 AU/ml, p less than 0.02). Coronary angiography performed within 24 hours after the last anginal episode showed a similar extent of coronary artery disease in the unstable and stable angina groups. However, intracoronary thrombi were observed in eight patients in the unstable angina group while no thrombus was noted in the stable angina group (chi 2 = 7.22, p less than 0.01). CONCLUSIONS We conclude that patients with unstable angina at rest have a reduced fibrinolytic activity and an increased incidence of intracoronary thrombi. It is postulated that elevated PAI-1 activity in the presence of coronary arterial wall injury may be an important factor leading to the development of acute coronary syndromes.

Clinical and anatomic determinants of the initial success of percutaneous transluminal coronary angioplasty were prospectively evaluated in 826 patients enrolled in the Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART). The 639 men and 187 women ranged in age from 31 to 85 years. Successful angioptasty (residual stenosis

The aim of this study was to test the hypothesis that either the cyclooxygenase inhibitor aspirin or the thromboxane A2receptor antagonist sulotroban exerts a direct myocardial effect that enhances myocardial salvage worded by reperfusion. Accordingly, 21 anesthetized dogs underwent suture occlusion of the left anterior descending coronary artery. At 2.5 h after occlusion, all dogs received intravenous streptokinase (20,000 U/kg y weight over 30 min) and were randomized to the following groups: group I (n = 7) received no additional treatment, group II (n = 7) received aspirin (5 mg/kg intravenously) and group III (n = 7) received sulotroban (10 mg/kg followed by 10 mg/kg per h intravenously). At 3 h after occlusion, the dogs underwent coronary reperfusion for the next 3 h.Myocardial infarct size as a percent of the hypoperfused zone was similar among dogs in group I (42 ± 8%), group II (41±10%) and group III (45±11 %). The incidence and the extent of myocardial hemorrhage were similar in all three study groups. Infarct size as a percent of the hypoperfused zone was significantly smaller in dogs without hemorrhage irrespective of treatment (35±9%m versus 63±5%, p< 0.01).In conclusion, 1) in the presence of 3 h coronary occlusion and reperfusion, neither a cyclooxygenase inhibitor nor a specific thromboxane A2receptor antagonist enhanced myocardial salvage by means of a direct myocardial effect as comp with reperfusion alone; 2) any potential benefits of combined thrombolytic and antiplatelet therapy are likely to be limited to their vascular effects (for example, reperfusion efficacy and prevention of reocclusion); and 3) myocardial hemorrhage may limit myocardial salvage afforded by coronary reperfusion.

The initial results, complications and early follow-up of 74 patients undergoing percutaneous balloon mitral valvuloplasty in seven hospitals participating in a multicenter registry are reported. Seventy-four patients with a mean age of 53 years had 75 valvuloplasty procedures performed over a 2.5 year period. Eighty-nine percent of the attempted procedures were completed and resulted in an increase in mean mitral valve area from 1.0 ± 0.04 to 2.0 ± 0.1 cm2(p < 0.0001); the valve area increased ≥50% of the baseline valve area in 73% of the patients.Major complications included procedure-related death (2.7%), cardiac tamponade (6.7%), systemic embolism (2.7%) and emergency surgery (6.7%). At a mean follow-up period of 14.6 months, the condition of the majority of patients had improved, and 89% of 55 patients treated only with valvuloplasty were in New York Heart Association functional class I or II.Thus, hemodynamic and clinical improvement can be obtained in the majority of patients with mitral stenosis treated with balloon valvuloplasty in multiple centers. However, suboptimal results and major complications occurred in a significant number of patients and may limit this procedure to use by experienced operators in hospitals with facilities for cardiac surgery.

Background: Lp-PLA 2 , an emerging marker of CV risk, generates products of oxidized LDL that may contribute to inflammation and apoptosis. Although Lp-PLA 2 is highly expressed in thin-cap fibroatheroma and ruptured plaques, its role in mediating lesion vulnerability remains unknown. Material and Methods: Patients were randomized to receive placebo or the selective Lp-PLA 2 inhibitor, darapladib, (40 or 80 mg po) for 14 days prior to carotid endartherectomy. In the post hoc analysis, caspase activities were measured in carotid plaques (colorimetric assays: AU/mg of protein) and correlated with inhibition of Lp-PLA 2 activity in plasma (radiometric assay) using Spearman’s rank method. Results: Caspase-8 (initiator) and -3 (effector) activities were measured as the index of apoptosis in carotid atheroma specimens. In the validation study, carotid atheroma (n=10) exhibited augmented levels of caspase activities compared to non-diseased vessels (n=8) (caspase-8: 4.74±0.3 vs 2.59±0.2; caspase-3: 10.2±0.9 vs 4.15±0.4 p2 activity and markers of apoptosis, plaque caspase activity was correlated with Lp-PLA 2 inhibition in plasma. Plaque caspase-8 and -3 correlated with inhibition of Lp-PLA 2 activity in plasma (caspase-8: r=-0.34, p=0.039; caspase-3: r=−0.51, p Conclusions: Inhibition of Lp-PLA 2 reduced activity of proapoptotic caspases in human atheroma. The results suggest that Lp-PLA 2 inhibition may attenuate noxious effects of oxidized LDL and promote lesion stabilization in high risk patients.

This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor, on biomarkers of cardiovascular (CV) risk.Elevated Lp-PLA(2) levels are associated with an increased risk of CV events.Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA(2) activity and other biomarkers.Baseline low-density lipoprotein cholesterol (LDL-C) was 67 +/- 22 mg/dl. Plasma Lp-PLA(2) was higher in older patients (or=75 years), in men, in those taking atorvastatin 20 mg, at LDL-Cor=70 mg/dl or high-density lipoprotein cholesterol (HDL-C)40 mg/dl, or in those with documented vascular disease (multivariate regression; p0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA(2) activity by approximately 43%, 55%, and 66% compared with placebo (p0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (or=70 vs.70 mg/dl) and HDL-C (40 vs.or=40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] -22% to -1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI -28% to +5%; p = 0.15) compared with placebo. The Lp-PLA(2) inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B(2)). No major safety concerns were noted.Darapladib produced sustained inhibition of plasma Lp-PLA(2) activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA(2) inhibition is associated with favorable effects on CV events.

Background: Atherosclerosis is a systemic disease with focal rupture of vulnerable plaque responsible for major clinical events. Several population-based studies indicate an association between lipoprotein-associated phospholipase A2 (Lp-PLA2) and cardiovascular events. Lp-PLA2 is emerging as a biomarker that may be a potential link between oxidized LDL cholesterol and multifocal plaque vulnerability.Content: Lp-PLA2 is produced by inflammatory cells of myeloid origin, is associated with circulating atherogenic lipoproteins (e.g., LDL), and is highly expressed in vulnerable plaques (de novo expression). Specificity of Lp-PLA2 toward polar phospholipids in oxidized LDL may contribute to the formation of downstream products (e.g., lysophosphatidylcholine and nonesterified fatty acids) that mediate processes intimately involved in plaque vulnerability in situ, including proinflammatory cell phenotype and macrophage death. Recent studies in patients with acute coronary syndrome (ACS) demonstrate that Lp-PLA2 and LDL measurements are not useful to assess the long-term cardiovascular risk shortly after the acute event, most likely because of the acute drop in LDL values that is commonly observed in ACS. However, when measured at later time points, Lp-PLA2 emerges as an independent predictor of the long-term cardiovascular risk, according to multivariate analysis.Summary: Lp-PLA2 is an intriguing marker of cardiovascular risk and may also be a marker of plaque activity/vulnerability. Despite these findings, unanswered questions still exist with respect to this enzyme and its biologic role in atherosclerosis. Addressing these questions will help clarify the clinical utility of measuring Lp-PLA2 in routine clinical practice in the context of other approaches for identifying high-risk patients.

Despite substantial progress in preventing adverse cardiovascular events with current therapeutic strategies, there remains an extensive residual risk of clinical events, particularly in high-risk patients. Because of the evidence implicating inflammation in the pathogenesis of atherosclerosis, identifying and targeting inflammatory pathways could help further reduce cardiovascular risk. There has been controversy regarding the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in atherosclerosis, partly because of the lack of simple animal models with a human-like pattern of Lp-PLA2 lipoprotein distribution. However, accumulating evidence from pathology, biology and epidemiology studies favors a pro-atherogenic rather than an atheroprotective role for the enzyme. In particular, Lp-PLA2 might play an important role in plaque vulnerability. As a result, additional studies are warranted to determine whether Lp-PLA2 inhibition improves plaque stability and ultimately clinical outcomes for high-risk patients.

Our purpose was to assess noninvasive imaging in detection of subclinical atherosclerosis and to examine novel invasive modalities to describe prevalence and temporal changes in putative characteristics of "high-risk" plaques.Conventional coronary imaging cannot identify "high-risk" lesions.Conventional (quantitative angiography and intravascular ultrasound [IVUS]) and novel imaging (IVUS-based palpography and gray scale echogenicity) were performed at baseline and 6 months later in 67 patients with diverse clinical presentations. Different imaging techniques were compared within a common segment defined by multislice computed tomography (MSCT).Compared with IVUS, the sensitivity, specificity, and positive and negative predictive value of MSCT for detecting significant plaque was 86%, 69%, 90%, and 61%, respectively. In coronary arteries with50% stenosis, there were no temporal changes in luminal and plaque dimensions measured by quantitative coronary angiography or IVUS; however, a significant reduction in abnormal strain pattern was detected on palpography (density high strain spots/cm: 1.6 +/- 1.5 vs. 1.2 +/- 1.4, p = 0.0123. These changes were mainly related to significant changes in patients who presented with ST-segment elevation myocardial infarction. The assessment of plaque echogenicity showed no temporal changes. There were no correlations between circulating biomarkers and quantifiable imaging parameters.Mild angiographic disease is associated with large atherosclerotic plaques on MSCT. Conventional invasive coronary imaging reveals static luminal and plaque dimensions on standard medical therapy with plaque hypoechogenicity remaining unchanged over the 6-month period. By contrast, palpography measurements of strain correlate with clinical presentation and significantly decrease on standard medical therapy. Novel imaging modalities, such as palpography, might provide insights into plaque biology and might eventually serve as intermediate end points in interventional trials.

The development of atherosclerotic vascular disease is invariably linked to the formation of bioactive lipid mediators and accompanying vascular inflammation. Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is an enzyme that is produced by inflammatory cells, co-travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL. Its biological role has been controversial with initial reports purporting atheroprotective effects of Lp-PLA 2 thought to be a consequence of degrading platelet-activating factor and removing polar phospholipids in modified LDL. Recent studies, however, focused on pro-inflammatory role of Lp-PLA 2 mediated by products of the Lp-PLA 2 reaction (lysophosphatidylcholine and oxidized nonesterified fatty acids). These bioactive lipid mediators, which are generated in lesion-prone vasculature and to a lesser extent in the circulation (eg, in electronegative LDL), are known to elicit several inflammatory responses. The proinflammatory action of Lp-PLA 2 is also supported by a number of epidemiology studies suggesting that the circulating level of the enzyme is an independent predictor of cardiovascular events, despite some attenuation of the effect by inclusion of LDL, the primary carrier of Lp-PLA 2 , in the analysis. These observations provide a rationale to explore whether inhibiting Lp-PLA 2 activity and consequent interference with the formation of bioactive lipid mediators will abrogate inflammation associated with atherosclerosis, produce favorable changes in intermediate cardiovascular end points (eg, biomarkers, imaging, and endothelial function), and ultimately reduce cardiovascular events in high-risk patients.

Death or myocardial infarction, the most serious clinical consequences of atherosclerosis, often result from plaque rupture at non-flow limiting lesions. Current diagnostic imaging with coronary angiography only detects large plaques that already impinge on the lumen and cannot accurately identify those that have a propensity to cause unheralded events. Accurate evaluation of the composition or of the biomechanical characteristics of plaques with invasive or non-invasive methods, alone or in conjunction with assessment of circulating biomarkers, could help identify high-risk patients, thus providing the rationale for aggressive treatments in order to reduce future clinical events. The IBIS (Integrated Biomarker and Imaging Study) study is a prospective, single-center, non-randomized, observational study conducted in Rotterdam. The aim of the IBIS study is to evaluate both invasive (quantitative coronary angiography, intravascular ultrasound (IVUS) and palpography) and non-invasive (multislice spiral computed tomography) imaging techniques to characterize non-flow limiting coronary lesions. In addition, multiple classical and novel biomarkers will be measured and their levels correlated with the results of the different imaging techniques. A minimum of 85 patients up to a maximum of 120 patients will be included. This paper describes the study protocol and methodological solutions that have been devised for the purpose of comparisons among several imaging modalities. It outlines the analyses that will be performed to compare invasive and non-invasive imaging techniques in conjunction with multiple biomarkers to characterize non-flow limiting subclinical coronary lesions.

Microwave energy was used to evaluate the treatment of vascular thrombus in a canine model of coronary thrombus. It was found that with the microwave energy, it was possible to coagulate and laminate intracoronary thrombus, providing a more effective resolution of intracoronary thrombus than with conventional balloon angioplasty. >

Background —Because saphenous vein grafts (SVGs) exhibit greater cellular heterogeneity and worse clinical outcomes than arterial grafts (AGs), we examined oxidative stress and lipid retention in different vascular conduits. Methods and Results —In a porcine model of graft interposition into carotid artery, superoxide anion (·O 2 − ) was measured at 2 weeks after surgery. SVGs demonstrated increased ·O 2 − production compared with AGs (SOD-inhibitable nitro blue tetrazolium reduction, P P 2 − , whereas the inhibitors of other pro-oxidant enzymes were ineffective. The change in oxidative stress was also reflected by lower activity of the endogenous antioxidant superoxide dismutase in SVGs than in AGs ( P 125 I-labeled LDL than AGs ex vivo ( P Conclusions —This study demonstrated significant differences in the biology of SVGs and AGs. SVGs exhibited higher oxidative stress, LDL accumulation, and the presence of oxidized epitopes. These findings suggest that proatherogenic changes in SVGs may commence early after surgical revascularization.

Coronary repair and restenosis are complex processes that likely differ from the established paradigm, which has been based on numerous observations with cultured smooth muscle cells and the response of non-coronary vascular beds to injury. Pluripotent mesenchymal ceils are present in the adventitia and may migrate into the region of underlying coronary lesions during the process of atherogenesis. The activation of these cells appears to play an important role in the development of restenosis. This includes fibroblast proliferation, their differentiation to myofibroblasts, and the synthesis of extracellular matrix proteins. Antisense oligomers against several cell cycle regulating genes inhibit cell proliferation and neointimal formation in various animal models. These compounds are pleiotropic, thus exerting their biological effects through several mechanisms. It remains to be determined whether the prevention of cell proliferation with antisense oligomers is sufficient to inhibit other important manifestations of vascular cell activation (eg, remodeling and lipid retention), which play roles in the development of coronary restenosis.

Recent findings demonstrate that adventitial fibroblasts (i.e., nonmuscle cells) are endowed with several characteristics previously attributed to medial SM cells. The response of the coronary artery to balloon angioplasty is associated with the activation of adventitial cells in a porcine model. They appear to be the most reactive in the arterial wall, as reflected by the extent of proliferation and the synthesis of collagen. Differentiation of adventitial cells, which acquire alpha-SM actin, illustrates the formation of vascular myofibroblasts, a ubiquitous cellular mechanism of tissue repair. Myofibroblasts are involved in remodeling of the adventitia and may contribute to the formation of the neointima after balloon-induced coronary injury. These findings suggest that at least some synthetic SM-like cells present in intimal lesions may originate from medial or adventitial nonmuscle cells. Myofibroblasts also appear to play a role in other cardiovascular abnormalities (e.g., vein graft remodeling), which raises the possibility of targeted therapies.

Transforming growth factor-β1 (TGF-β1) plays a central role in tissue repair owing to its modulating effects on cell growth and the synthesis of extracellular matrix. We have previously shown that adventitial fibroblasts differentiate to myofibroblasts after endoluminal injury, thereby contributing to arterial remodeling. Since TGF-β1 exerts several biologic actions attributed to myofibroblasts, we examined its role in myofibroblast formation in a porcine model of balloon overstretch coronary artery injury. TGF-β1 transcripts were induced in numerous adventitial cells 2 days after injury (47±10%, P 14 days after injury), the decrease in TGF-β1 coincided with the disappearance of adventitial myofibroblasts, whereas the neointima exhibited longer TGF-β1 expression. In conclusion temporal and spatial relationships between TGF-β1 and myofibroblast formation suggest an important role for autocrine TGF-β1 in the phenotypic modulation of vascular fibroblasts. Induction of TGF-β1 expression may provide a differentiation signal for adventitial fibroblasts to become myofibroblasts, which affect arterial remodeling via their mechanical and synthetic properties.