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Background: We have reported that immunization with the apoB-100 derived peptide p210 reduces atherosclerosis and aortic aneurysm formation/rupture, through modulation of CD8+ T cells. It remains unclear how an exogenous peptide like p210 enters dendritic cells for antigen presentation by MHC-I to CD8+ T cells. The p210 peptide sequence is located within the proteoglycan (PTG) binding site of apoB-100, which is a known alternative mechanism for cell internalization of LDL. Antigens internalized by cell surface PTG binding are cross-presented on the MHC-I molecule. We therefore tested the mechanism of p210 internalization by dendritic cell (DC) surface PTG binding and investigated the CD8+ T cell function in response to p210 antigen presentation. Methods and Results: Bone marrow derived DCs from apoE-/- mice were primed with fluorescently tagged p210 (FITC-p210) for 4 hours in vitro. There was significantly increased FITC internalization in DCs treated with FITC-p210 compared to FITC alone (24.3±2.7% vs. 6.6±0.8%; P Conclusion: Internalization of p210 is mediated in part by DC surface PTG binding, resulting in significantly reduced CD8+CD25+FoxP3+ regulatory T cells and increased cytolytic activity, suggesting unopposed CD8+ T cell effector function. Our results support the mechanism of p210 internalization by DC surface PTG increasing CD8+ T cell function.

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.

Background Multi-contrast weighted imaging is a commonly used cardiovascular magnetic resonance (CMR) protocol for characterization of carotid plaque composition. However, this approach is limited in several aspects including low slice resolution, long scan time, image mis-registration, and complex image interpretation. In this work, a 3D CMR technique, named Multi-contrast Atherosclerosis Characterization (MATCH), was developed to mitigate the above limitations. Methods MATCH employs a 3D spoiled segmented fast low angle shot readout to acquire data with three different contrast weightings in an interleaved fashion. The inherently co-registered image sets, hyper T1-weighting, gray blood, and T2-weighting, are used to detect intra-plaque hemorrhage (IPH), calcification (CA), lipid-rich necrotic core (LRNC), and loose-matrix (LM). The MATCH sequence was optimized by computer simulations and testing on four healthy volunteers and then evaluated in a pilot study of six patients with carotid plaque, using the conventional multi-contrast protocol as a reference. Results On MATCH images, the major plaque components were easy to identify. Spatial co-registration between the three image sets with MATCH was particularly helpful for the reviewer to discern co-existent components in an image and appreciate their spatial relation. Based on Cohen’s kappa tests, moderate to excellent agreement in the image-based or artery-based component detection between the two protocols was obtained for LRNC, IPH, CA, and LM, respectively. Compared with the conventional multi-contrast protocol, the MATCH protocol yield significantly higher signal contrast ratio for IPH (3.1 ± 1.3 vs. 0.4 ± 0.3, p

Objectives : The predictive value of thoracic aortic calcium (TAC) scores for coronary artery calcium (CAC) conversion (CAC > 0) has not been fully evaluated. Methods : We studied 1648 asymptomatic subjects (mean age 52 ± 9 years, 54% male) with baseline CAC = 0 who underwent repeat CAC scanning 5 years later (range 3–14 years). TAC was assessed in the ascending and descending aorta. CAC and TAC were measured using Agatston scores. The cohort was categorized by baseline TAC scores: TAC = 0 ( n = 1381 subjects), TAC 1–9 ( n = 54), TAC 10–99 ( n = 132) and TAC ≥ 100 ( n = 81). Logistic regression was used to examine the predictive value of baseline TAC scores for CAC > 0 on repeat scans. Results : On repeat scanning, 380 subjects (23%) developed CAC > 0. The frequency of CAC > 0 increased progressively across baseline TAC (TAC = 0, TAC 1–9, TAC 10–99 and TAC ≥ 100) 22%, 26%, 26% and 37%, respectively ( P for trend = 0.0025). Univariate analysis showed baseline TAC ≥100 was a significant predictor of CAC > 0 in repeat scans, while either TAC 1–9 or TAC 10–99 were not, OR 2.10 [CI 1.32–3.36], P = 0.002; OR 1.25 [CI 0.67–2.33], P = 0.5; OR 1.24 [CI 0.82–1.87], P = 0.3, respectively. In multivariable analysis, TAC ≥100 OR 1.90 [CI 1.08–3.33], P = 0.026, was a significant predictor of CAC > 0, along with age, male gender, diabetes, hypertension, hypercholesterolemia and time between scans. Conclusions : The likelihood of conversion to CAC > 0 increases with increasing TAC scores. TAC ≥ 100 is an independent predictor of CAC conversion. Subjects with CAC = 0 and extensive TAC (TAC ≥ 100) may merit earlier repeat scanning than those with no TAC or lower TAC scores.

As a growing number of patients infected with human immunodeficiency virus (HIV) have access to antiretroviral therapy and achieve virologic suppression, the focus of clinical care is shifting from treating the infectious complications of advanced immunodeficiency to managing and preventing chronic disease. The aging of the HIV-positive population and increased rates of chronic disease complications in the setting of HIV infection have increased the impact of noncommunicable diseases such as coronary heart disease (CHD). The effect of HIV on CHD is independent of traditional cardiovascular risk factors and antiretroviral medications and is likely due in part to the chronic inflammation and immune activation underlying HIV infection. This article describes the current state of epidemiologic knowledge on CHD in HIV infection. It highlights key studies in the field and summarizes epidemiologic data with respect to traditional and novel CHD risk factors, specialized clinical subgroups, and broader cardiovascular outcomes.

“ An invasion of armies can be resisted but not an idea whose time has come.” —Victor Hugo. Vaso-occlusive disease resulting from atherosclerosis and thrombosis is the leading cause of death and morbidity in the United States and other industrialized nations. Although the precise cause of atherosclerosis is unclear, an emerging paradigm suggests that atherosclerosis involves multiple pathways in which lipoprotein entry and retention, injury to the vessel wall from diverse stimuli, and an associated long-term inflammatory and immune response seem to play a key role.1–4 Dyslipidemia characterized predominantly by elevated levels of one or more circulating non-HDL cholesterol lipoproteins [LDL, VLDL, lipoprotein(a), triglycerides] and/or reduced HDL cholesterol is one of the key risk factors for atherosclerosis and cardiovascular disease.5–16 Over the past several years, a number of large, prospective, randomized, controlled clinical trials have demonstrated both angiographic and clinical benefits of lipid-lowering therapy, with a significant reduction in fatal and nonfatal cardiovascular events.17–23 These studies have primarily targeted LDL cholesterol through pharmacotherapy (mostly statins), with or without dietary counseling, lifestyle modification, or surgery (intestinal bypass in Program on the Surgical Control of the Hyperlipidemias [POSCH] trial). Overall, a significant and clinically worthwhile relative risk reduction ranging from 20% to 40% in major cardiovascular events has been achieved with these strategies, without significant adverse effects or increased noncardiovascular mortality. These remarkable results prompted Brown and Goldstein24 to predict that heart attacks will be gone with the century. This clearly reflects an overoptimistic point of view, because 60% to 70% of adverse cardiovascular events continue to occur despite LDL-lowering therapy. Potential reasons why cardiovascular events may continue to occur despite low LDL levels or despite LDL-lowering therapy include the following: (1) we may not be lowering LDL cholesterol to optimal levels, because optimal levels are not clearly …

We investigated the effects of magnesium on acute platelet-dependent stent thrombosis in an ex vivo porcine arteriovenous shunt model of high-shear blood flow. Control nitinol stents were expanded to 2 mm in diameter in a tubular perfusion chamber interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100 s −1 for 20 minutes (n=156 perfusion runs in 10 swine). Animals were treated with intravenous heparin or MgSO 4 alone (2 g bolus over 20 minutes, followed by 2 g/h infusion) and combined heparin plus MgSO 4 in random fashion. Effects on thrombus weight (TW), platelet aggregation, bleeding time, activated clotting time, mean arterial blood pressure, and heart rate were quantified. Data points in the magnesium-treated animals were examined within 20 minutes after bolus (Mg-early) and >40 minutes after bolus (Mg-late). Stent TW (20±3 mg, pretreatment) was reduced by 42±21%, 47±19%, 48±16%, 67±12%, and 86±8% in the groups treated with Mg-early alone, Mg-late alone, heparin alone, heparin+Mg-early, and heparin+Mg-late, respectively (all P P P r =−0.70, P =0.002). In conclusion, treatment with intravenous MgSO 4 produced a time-dependent inhibition of acute stent thrombosis under high-shear flow conditions without any hemostatic or significant hemodynamic complications. Thus, magnesium may be an effective agent for preventing stent thrombosis.

Background —The clinical benefits of lipid lowering with statins are attributed to changes in plaque composition leading to lesion stability, but supporting clinical data from human studies are lacking. Therefore, we investigated the effect of 3 months of pravastatin treatment on composition of human carotid plaques removed during carotid endarterectomy. Methods and Results —Consecutive patients with symptomatic carotid artery stenosis received 40 mg/d pravastatin (n=11) or no lipid-lowering therapy (n=13; control subjects) for 3 months before scheduled carotid endarterectomy. Carotid plaque composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Plaques from the pravastatin group had less lipid by oil red O staining (8.2±8.4% versus 23.9±21.1% of the plaque area, P P P P P P P P Conclusions —Pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans.

OBJECTIVES The purpose of this study was to determine the temporospatial expression of tenascin-C (TnC) in balloon-injured rat and porcine arteries. BACKGROUND Recent studies suggest that cell migration, in addition to cell proliferation, is a critical component of neointima formation after vascular injury. We have previously shown that adventitial myofibroblasts synthesize growth factors that contribute to the formation of neointima after arterial injury. We have also shown that the extracellular matrix protein, TnC, regulates cell migration. Consequently, we investigated the temporospatial expression of TnC by myofibroblasts after vascular injury. METHODS In situ hybridization and immunohistochemistry were used to investigate the temporospatial expression of TnC in injured arteries. Northern and Western blots were used to determine the in vitro expression of TnC. RESULTS In situ hybridization revealed that the major site of TnC expression early after vascular injury was the adventitial myofibroblasts. Immunohistochemical staining demonstrated that TnC expression began in adventitial myofibroblasts three days after injury. Tenascin-C expression, however, did not persist in this region. Rather, it moved progressively across the vascular wall toward the luminal surface. By one week, TnC expression reached the developing neointima. In vitro, myofibroblasts did not express TnC mRNA under basal conditions. In contrast, angiotensin II and PDGF-BB, factors that have been implicated in remodeling of balloon-injured arteries, markedly upregulated TnC mRNA. CONCLUSIONS Tenascin-C is expressed in response to balloon injury. Tenascin-C expression begins with adventitial myofibroblasts. Over a period of 7 to 14 days, expression moves progressively across the vessel wall to the neointima. We hypothesize that adventitial myofibroblasts are actively involved in the formation of neointima and that TnC facilitates migration of these cells during adventitial remodeling.

Background —In patients with acute myocardial infarction (AMI) undergoing thrombolytic therapy, an elevated troponin level on admission is associated with a lower reperfusion rate and a complicated clinical course. Whether an elevated troponin level on admission similarly predicts an adverse outcome in patients undergoing primary angioplasty is currently unknown and was investigated in the present study. Methods and Results —Cardiac troponin I (cTnI) was determined on admission in 110 consecutive patients with AMI associated with ST-segment elevation or left bundle branch block who underwent primary angioplasty. Fifty-four patients (49%) had an elevated cTnI (≥0.4 ng/mL) on admission. In patients with elevated cTnI, primary angioplasty was less likely to achieve TIMI 3 flow (as classified by the Thrombolysis in Myocardial Infarction trial) in univariate (76% versus 96%, P =0.03) or in multivariate (odds ratio 0.1, 95% CI 0.02 to 0.54) analysis. Patients with elevated cTnI were more likely to develop congestive heart failure (23% versus 9%, P P =0.006). Elevated cTnI remained a significant predictor of the composite end point after controlling for other clinical data that were available early in the course, including time to presentation and angiographic results (relative risk 5.2, 95% CI 1.03 to 26.3). During a follow-up of 426±50 days, elevated admission cTnI was a predictor of cardiac mortality (11% versus 0%, P =0.012), adverse cardiac events (cardiac mortality or nonfatal reinfarction; 19% versus 5.4%, P =0.04), and adverse cardiac events plus target vessel revascularization (32% versus 14%, P =0.054). Conclusions —In patients with ST-segment elevation AMI, an elevated cTnI on admission is associated with an increased risk of primary angioplasty failure and a more complicated clinical course.

This article will review the results of recent clinical trials evaluating low molecular weight heparins (LMWHs) in the management of patients with acute coronary syndromes of unstable angina and non-ST segment elevation MI. Low molecular weight heparins are a new class of anticoagulants that have a number of advantages over unfractionated heparin (UFH) leading to their increasing use for thrombotic vascular disorders. There is convincing evidence that LMWH is more effective than placebo and at least as effective as UFH in reducing the hard end points of death and recurrent myocardial infarction. Convincing evidence for a superior efficacy is mostly limited to the least robust but most prevalent end point of recurrent angina, and benefits appear to be confined predominantly to high-risk patients. The benefits are sustained long-term, but there appears to be no incremental benefit with prolonged treatment. The risk for major bleeding is approximately equivalent to UFH, but minor hemorrhage is clearly increased, especially with vascular instrumentation. The increased bleeding risk together with its long half-life and absence of specific antidote warrants exercising caution when using LMWH with coronary intervention. Low molecular weight heparins have the potential of being cost-neutral or even cost-saving by reducing resource utilization, especially in the setting of aggressive interventional practice pattern. Last, the issue of whether one LMWH preparation is more effective and cost-effective than others remains an open question that can be answered only by direct head-to-head comparison of different LMWH preparations in randomized trials. In conclusion, subcutaneous weight-adjusted LMWH is as effective and safe as intravenous UFH in the management of patients with acute coronary syndromes. The logistic ease of administration without the need for monitoring anticoagulation appears to be the major advantage over UFH.

Acute coronary syndromes (unstable angina, acute myocardial infarction, and ischemic sudden death) result from coronary thrombosis superimposed on an atherosclerotic plaque. Thrombosis is generally a consequence of disruption of the atherosclerotic plaque in the form of a fissure/rupture in the fibrous cap overlying a lipid-rich pool or superficial endothelial erosion covering a smooth muscle and proteoglycan-rich matrix with or without a lipid-core. Approximately 2/3 of acute coronary syndromes evolve from atherosclerotic plaques that are minimally or mildly obstructive of the lumen before the acute event. Inflammation with accumulation of activated mononuclear cells may play a potential role in plaque disruption through the elaboration of proteases, such as matrix degrading neutral metalloproteinases and other proteases, inhibition of function and/or survival, or promotion of apoptosis of matrix synthesizing smooth muscle cells. Inflammation may also contribute to thrombosis after plaque disruption by providing a source for tissue factor in the plaque. Inflammation in the plaque may result from accumulation of modified lipids, oxidant and hemodynamic stress, and infectious agents, such as Chlamydia pneumoniae or pro-inflammatory triggers from distant sites of infection and inflammation (eg, chronic gingivitis and chronic bronchitis). Improved insights into the pathophysiology of plaque disruption and thrombosis are likely to provide new and improved methods of stabilizing atherosclerotic disease process.

The efficacy of abciximab and moderate dose heparin in attaining reperfusion in acute MI was tested in a multicenter pilot study. Patients with acute MI of less than 6-hr onset triaged to primary PTCA received intravenous abciximab bolus and infusion and heparin (70 u/kg) in the emergency room. Mean time to angiography from administration of abciximab was 34 +/- 23 min. TIMI flow rates were: grade 0-62%, grade I-20%, grade II-9%, and grade III-9%. Primary PTCA was performed with 100% success rate. Access site bleeding occurred in 10% of patients with no incidence of intracranial bleeding. TIMI II/III flow rates were 50% in a patient subset where angiography was delayed by 45 min. While not an alternative to thrombolytics in AMI, abciximab administration in the emergency room in patients triaged to PTCA may be beneficial in situation where door to needle time is delayed as TIMI II/III flows may be attained in some patients. Cathet. Cardiovasc. Intervent. 48:430-434, 1999.

Leukaemia inhibitory factor (LIF) and interleukin (IL)-6 are members of a cytokine group that share a common signal transducer gp130 and induce pleiotropic biological effects in cells of diverse lineage. In monocytes, LIF facilitates differentiation, which may stimulate the biosynthesis of tissue factor (TF) that initiates the coagulation cascade. We tested the hypothesis that LIF would enhance TF expression in human monocyte-derived macrophages (MDMs). Human peripheral blood mononuclear cells separated from whole blood by density centrifugation were allowed to differentiate into MDMs in primary culture, and were then exposed to LIF, IL-6 and oncostatin M (OSM) for 24 h. LIF and IL-6 receptors, and gp130 were demonstrated in MDMs by immunocytochemistry and RT-PCR. TF procoagulant activity (TF-PCA) was measured by recalcification clotting time and TF protein by Western blotting. The results show that both TF procoagulant activity and TF protein increased significantly in response to LIF over the concentration range of 1-100 nM (P < 0.03). Although OSM and IL-6 tended to enhance TF expression by MDMs, the increase did not reach statistical significance. Anti-LIF receptor and anti-gp130 antibodies attenuated the effect of LIF on TF expression as assayed by both bioassay and flow-cytometry. In conclusion, LIF increases TF-PCA and TF protein in MDMs, and specific anti-LIF receptor antibodies attenuate this effect. Thus, LIF may regulate by a gp130-dependent pathway macrophage-mediated procoagulant function in diverse pathological states involving inflammation and thrombosis and seems to serve as an important mediator at the interface between these processes.

Plasma total and low-density lipoprotein (LDL) cholesterol are established risk factors for atherosclerotic vascular disease and may also contribute to a prothrombotic risk via enhanced platelet reactivity. This study examines whether high-density lipoprotein (HDL) cholesterol, which is inversely correlated with coronary artery disease, is associated with a reduced thrombogenic potential. Platelet thrombus formation was evaluated by exposing porcine aortic media placed in Badimon perfusion chambers to flowing nonanticoagulated venous blood for 5 minutes at a shear rate of 1,000 s(-1). Forty-five subjects, 23 normal (LDL 104 +/- 31, HDL 50 +/- 15 mg/dl) and 22 hypercholesterolemic (LDL 181 +/- 45, HDL 41 +/- 10 mg/dl) patients without coronary artery disease were studied. Platelet aggregation and CD62 antigen expression, and assay for circulating prothrombotic factors were also performed. In univariate analysis platelet thrombus formation correlated with weight (r = 0.33, p = 0.03), diastolic blood pressure (r = 0.39, p = 0.01), HDL cholesterol (r = -0.45, p = 0.003), total/HDL cholesterol (r = 0.43, p = 0.004) and LDL/HDL (r = 0.38, p = 0.01) ratios, and platelet CD62 expression (r = 0.41, p = 0.02). In multiple regression analysis only HDL cholesterol showed significant correlation with platelet thrombus formation (p = 0.03). Platelet aggregation and circulating prothrombotic factors did not correlate with platelet thrombus formation. A comparison between normal and hypercholesterolemic subjects revealed enhanced thrombus area (0.026 +/- 0.20 vs 0.045 +/- 0.039 mm2/mm; p = 0.04), resting CD62 expression (6 +/- 7% vs 15 +/- 10% positive platelets, p = 0.02), and platelet aggregation (16.7 +/- 5.2 vs 21.7 +/- 6.7 ohms, p = 0.04) in hypercholesterolemic subjects. Our results demonstrate that HDL cholesterol is a significant independent predictor of ex vivo platelet thrombus formation.

OBJECTIVES This study was performed to test the hypothesis that tenascin-C (TN-C), an extracellular matrix (ECM) protein with counteradhesive chemotactic and vascular growth-promoting effects, is expressed in “arterialized” human saphenous vein grafts (SVGs). BACKGROUND Tenascin-C is expressed in the vessel wall after vascular injury in the experimental model, where it has been implicated in the formation of neointima. Overexpression of TN-C has also been implicated in the development and progression of pulmonary hypertension. Saphenous vein grafts are exposed to hemodynamic stress when interposed in the arterial circulation and mechanical stress upregulates expression of TN-C, whereas stress-relaxation suppresses its synthesis. We hypothesized that the hemodynamic stress of increased arterial pressure could also induce TN-C expression in SVG. METHODS We examined the expression of TN-C protein and mRNA in normal vein and “arterialized” human SVG using immunohistochemistry and in situ hybridization, respectively. RESULTS TN-C protein was not detected in control human saphenous veins; however, it was uniformly and strongly expressed in the adventitia and media of patent human vein grafts, with minimal or no expression in the neointima (n = 27, 100%). In situ hybridization showed that TN-C mRNA was not detected in the neointima, but was strongly upregulated in the adventitia and media, corroborating immunostaining data (n = 10, 100%). Unlike patent SVG, TN-C was not expressed in the adventitia of occluded grafts, except for a low level of expression around the newly formed vessels in neointima (n = 5, 100%). Smooth muscle cell-specific staining demonstrated that the lack of expression of TN-C in occluded vein grafts is not due to the lack of presence of smooth muscle cells in the graft. CONCLUSIONS These findings suggest that placement of a venous graft in the arterial system leads to expression of TN-C, which may in turn facilitate graft remodeling. Conversely, loss of flow and intravascular pressure, associated with vein graft occlusion, is accompanied by disappearance of TN-C expression.

Ischemic heart disease, a consequence of coronary atherosclerosis, is the leading cause of death in the United States and developing countries. The clinical manifestations of coronary atherosclerosis range from asymptomatic state and stable angina, to acute coronary syndromes, such as unstable angina, acute myocardial infarction (MI), and many cases of sudden cardiac death. Acute coronary events are the first clinical expression of coronary atherosclerosis in 30% to 40% of cases. A better understanding of the pathophysiology of acute coronary syndromes could provide improved preventive and therapeutic strategies against coronary artery disease. Recent studies have challenged the old paradigm, which was based on the notion that coronary syndromes resulted from gradual and progressively luminal obstruction (stenosis) caused by growth of the atherosclerotic plaque. In the new paradigm, plaque disruption and thrombosis, the vulnerability to which is determined by intrinsic characteristics of the plaque (plaque vulnerability) and extrinsic triggers rather than the stenosis severity, are the most important determinants of the more lethal clinical manifestations of coronary atherosclerosis.* *References 11,16,17,20,21,24,25,27,29,30,94,95,98 Coronary artery disease progresses in a nonlinear and often unpredictable fashion leading to a rapid worsening of coronary luminal obstruction, including the sudden development of total or near total occlusion. This rapid change is largely related to superimposition of a thrombus on top of a disrupted plaque.25 Several studies have demonstrated a high prevalence of coronary thrombosis in acute coronary syndromes with an underlying substrate of plaque-cap fissure or rupture in 60% to 80% or superficial plaque-endothelial erosions in 20% to 40%.* Serial angiography has revealed an interesting angiographic-clinical paradox whereby 60% to 70% of acute coronary syndromes (and by inference plaque disruptions with thrombosis leading to total or subtotal occlusion) evolve from lesions that are non–flow-limiting with only a mild to moderate luminal stenosis even though severely stenotic lesions are more likely to progress to total occlusion over time.1,2,36,61 Stress testing in patients with known chronic coronary artery disease has also shown that MI often occurs in coronary territories that did not produce stress-induced ischemia months prior to development of MI.77 The apparent paradox may be largely explained by the fact that mildly stenotic lesions outnumber the severely stenotic lesions by a factor of 5 to 10 and that angiography often underestimates the extent of the plaque as well as the severity of anatomic cross-sectional narrowing that is observed in autopsy studies.82 Furthermore, a rapid transition of a mildly stenotic lesion to total occlusion is more likely to result in a clinical event, because of a low likelihood of protective collaterals, compared with when a severely stenotic lesion becomes totally occluded. Finally, mildly obstructive plaques are often large and may be subject to a greater degree of wall stress because of a larger luminal diameter.62,81,96

Background —Tenascin is a large extracellular matrix glycoprotein generally found in adult tissues undergoing active remodeling such as healing wounds and tumors. To determine the potential role of tenascin-C (TN-C) in the pathophysiology of atherosclerosis, we investigated the pattern of expression of TN-C in human coronary atherosclerotic plaques. Methods and Results —Immunohistochemical staining and in situ hybridization demonstrated minimal and random expression of TN-C in fibrotic but lipid-poor atherosclerotic plaques. In contrast, all plaques with an organized lipid core or ruptured intimal surface strongly expressed TN-C, which was preferentially concentrated around the lipid core, shoulder regions, and ruptured area of the plaques but not in the fibrous cap. TN-C was not detected in normal arterial tissue. To identify the cellular source of TN-C, the plaques were stained with smooth muscle cell– and macrophage-specific antibodies. TN-C expression correlated with the infiltration of macrophages. Northern blot and immunoprecipitation analysis showed that macrophages expressed 7.0-kb TN-C mRNA and 220-kDa protein. Reverse transcription–polymerase chain reaction of total RNA derived from macrophages showed that they express the small isoform of TN-C. Zymogram analysis revealed that macrophages markedly increased MMP-9 expression. Conclusions —This study demonstrates that the level of TN-C expression correlates with the degree of inflammation present, not with plaque size. In addition, cultured macrophages have the capacity to express the TN-C gene. These findings suggest the significance of macrophages in the remodeling of atherosclerotic plaque matrix composition.

See related article, pages 1589–1596 The prevalence of obesity, especially among adolescents, has increased considerably over the past 20 years because of increased caloric intake and reduced physical activity. It has been estimated that 20% of the world’s population is overweight and nearly 300 million are obese (BMI >30 kg/m2).1,2 Excess body weight and obesity are associated with the development of metabolic syndrome and type II diabetes, both of which are associated with insulin resistance and increased risk of cardiovascular complications.1,2 Atherothrombotic vascular disease, resulting from a complex interplay between dyslipidemia and vascular immunoinflammatory processes, is responsible for a majority of the excess morbidity and mortality that characterizes metabolic syndrome and type II diabetes.1,2 Several studies have shown that obesity is associated with activation of inflammatory pathways and that inflammatory responses are associated with impaired insulin signaling and insulin resistance.3–8 Considerable progress has been made in the last 2 decades in our understanding of molecular events that link obesity to inflammation, insulin resistance, type II diabetes, and enhanced vascular disease. Obesity-mediated skeletal muscle insulin resistance has been linked to defects in cellular signaling events triggered by insulin.3–8 In obesity, the skeletal muscle levels of several kinases such as protein kinase C isoforms (PKC), I Kappa B Kinase-β …

“For every complex problem there is a simple solution—and it’s wrong.” — H.L. Mencken Atherosclerosis is a highly prevalent disease that results from a complex interplay between lipids, endothelial cells, immunoinflammatory cells, cytokines, extracellular matrix, and neovascularization.1 Several lines of evidence suggest that increased adventitial and plaque neovascularity, commonly observed in murine and human atherosclerosis, plays an important role in progression and, possibly, destabilization of atherosclerosis.1–9 Increased plaque neovascularity may contribute to plaque progression by its link to inflammation, as a source of intraplaque hemorrhage and plaque lipid (Figure).1,5,7–9 Schematic illustrates the potential mechanisms of plaque neoangiogenesis and its potential role in atherosclerotic plaque progression. The putative mechanism by which oral DNA Vaccine against Flk-1 (fetal liver kinase or VEGFR2)-expressing cells may inhibits angiogenesis and plaque progression is also shown. The red arrows indicate the potential adverse aspects of such a therapeutic strategy. VEGF indicates vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; IL-8, interleukin-8. See page 1095 The precise mechanisms contributing to increased plaque neovascularity remain to be defined; however, inflammation and one or more angiogenic growth factors have been implicated. One of the pathways for angiogenesis leading to neovascularization involves the family of vascular endothelial growth factor(s) (VEGF) and their receptors (VEGFR). Therefore, VEGF and VEGFR mediated angiogenesis has emerged …

It has recently been proposed that asymptomatic diabetic patients undergo routine screening for subclinical atherosclerotic disease using myocardial perfusion scintigraphy. We herein analyze the expected cost and benefit associated with such a conditional test-treatment strategy (scintigraphic testing followed by statin treatment in positive test responders) in comparison to an unconditional treatment strategy (no testing and statin treatment in all). This analysis shows that unconditional treatment is the dominant strategy, costing 24% less ($3.2 billion) and preventing 25% more (16,800) atherosclerotic events annually on a national basis.

American College of Cardiology Foundation ### American Heart Association View this table: ACCF/AHA/CDC Consensus Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats—Participants’ Relationships With Industry

On March 4, 2015, Kanu Chatterjee, MBBS, a beloved physician, cardiologist, healer, teacher, and charismatic mentor, passed away peacefully in Iowa City, Iowa, after a brief battle with cancer. His passing has created an irretrievable loss for the field of cardiovascular medicine, because he was the essence of a clinician-teacher-investigator. Kanu was soft-spoken, kind, and wise; he was a practitioner of extraordinary skill, and spiritual. We were privileged to know this gentle giant of cardiology. Dr Kanu Chatterjee was born in Bangladesh, India, and received his medical degree from the R. G. Kar Medical College, Calcutta, India, while still living in a refugee camp in Calcutta. He moved to England in 1963, where he completed additional training in medicine and cardiology at St. George’s Hospital and the Royal Brompton Hospital, earning membership in the Royal College of Physicians of Edinburgh and London. Kanu rapidly established his reputation as a brilliant clinical cardiologist. In 1970, at the urging of 2 cardiologists at Cedars-Sinai Medical Center (Howard Allen, MD, and Harvey Alpern, MD, whom he met at St. Georges Hospital in London) as well as Graham Miller, PhD, of London, H. J. C. Swan, MD, then the director of cardiology at Cedars-Sinai, recruited Kanu to join …

Background: Besides its anticoagulant effects, heparin is known to alter platelet (PLT) function. We examined the effects of unfractionated heparin on PLT function in patients with stable coronary artery disease (CAD). Methods and Results: PLT function was evaluated by whole-blood flow cytometry to detect PLT CD62 expression and by impedance aggregometry to assess platelet aggregation (PA) before and after bolus intravenous administration of low-dose heparin (2713 ± 1231 U) in 16 patients undergoing coronary angiography (group 1) and high-dose heparin (7937 ± 2414 U) in 16 patients undergoing coronary angioplasty (group 2). Activated clotting time (ACT) and plasma antifactor-Xa heparin levels also were measured. Heparin increased PLT CD62 expression, which was significantly more pronounced in group 1 patients with plasma heparin levels less than 0.7 U/mL and ACT of 222 ± 52 seconds compared with group 2 patients with heparin levels greater than 0.7 U/mL and ACT of 365 ± 86 seconds (8 ± 9 v -1 ± 4% change in resting PLTs, P = .01, and 11 ± 12 v 1 ± 6% increase in adenosine diphosphate (ADP) [5 μM]-stimulated PLTs, P = .02). Heparin produced a slight increase in PA in group 1 patients (1.4 ± 5.3 ohms) as compared with the group 2 patients, where it significantly suppressed PA (-3.0 ± 5.3 ohms, P < .05 v group 1). A strong and statistically significant negative correlation between change in platelet CD62 expression and heparin concentration was observed in group 1 patients ( r = -.5, P = .05, —ADP; r = —.65, P = .006, +ADP), whereas this relationship was weak and did not reach statistical significance in group 2 patients ( r = -0.4, P = .2, -ADP; r = .11, P = 0.9; +ADP). Conclusion: Bolus administration of intravenous heparin augmented PLT activation in patients at clinically relevant anticoagulant concentrations (

Abstract —Oxidation of LDL is associated with degradation of phosphatidylcholine into platelet-activating factor (PAF)–like phospholipids and lysophosphatidylcholine (LPC). Exposure of cultured human smooth muscle cells to PAF and LPC in a concentration of 25 μmol/L was found to result in complete cell death, as assessed by the MTT cytotoxicity assay and cell counting. Addition of 50 μg/mL apolipoprotein A-I– and apolipoprotein A-I Milano –containing phospholipid particles completely inhibited this cytotoxicity. Phospholipid complexes alone were almost as effective, whereas free apolipoprotein A-I Milano and albumin were without effect, suggesting that the effect was phospholipid dependent. Experiments using [ 14 C]LPC demonstrated that apolipoprotein A-I– and apolipoprotein A-I Milano –containing phospholipid particles effectively bind LPC. The results show that HDL-like phospholipid particles effectively inhibit the toxic effect of phospholipids and other lipid-soluble factors. The ability of HDL to inhibit the proinflammatory and toxic effects of phospholipids generated during oxidation of LDL may be responsible for part of the antiatherogenic properties of HDL.

The failure of a well-designed, randomized trial of granulocyte colony-stimulating factor (G-CSF) therapy to significantly improve cardiac function after acute myocardial infarction, despite substantial bone marrow cell mobilization, is reported by Engelmann et al. ([1][1]) in this issue of the

The extracellular matrix protein tenascin-C is a multidomain protein that regulates cell adhesion. We used two different smooth muscle cell subtypes derived from adult and newborn rat aorta to investigate the interaction of tenascin-C or its various domains with these cells using an adhesion assay. Newborn cells were three times more adherent to tenascin-C than adult cells. Tenascin C-adhering cells remained round, whereas they spread rapidly on a fibronectin substrate. Adhesion assays showed the interaction between tenascin-C and newborn cells to be predominantly RGD-independent. Mg2+ increased newborn cell adhesion to tenascin-C in a concentration-dependent manner, whereas Ca2+ had no effect. To analyze the structure-function relationships of different domains of tenascin-C, we used recombinant full-length fibronectin-like and fibrinogen-like domains and various subdomains corresponding to the alternatively spliced regions of tenascin-C. The cells adhered to the fibrinogen-like domain but not to the fibronectin-like domain or its subdomains. As with the intact tenascin-C molecule, adherent cells remained round, and the Mg2+, but not Ca2+, promoted this interaction. The interaction of cells with the fibrinogen-like region was further mapped to a 30-amino acid peptide located near the carboxyl-terminal part of the tenascin-C molecule. The same 30-amino acid peptide was active in promoting cell migration. Our results provide a basis for understanding the mechanism of interaction of tenascin-C with smooth muscle cells and a framework for isolating membrane binding sites that mediate the cellular responses to this molecule.

Although the use of composite end points in clinical trials has increased in recent years, few data are available on the validity of such an approach. In the Thrombolysis In Myocardial Infarction (TIMI) 4 and 5 trials, we set out to validate prospectively the nonfatal components of the "unsatisfactory outcome" end point. This end point consisted of the in-hospital occurrence or observation of new-onset severe congestive heart failure/shock, left ventricular ejection fraction

Background: Nitric oxide (NO) plays an important role in modulating platelet-vessel wall interaction following vascular injury. We examined the effects of local infusion of an ultra- short-acting NO-releasing compound: NO adduct of N, N'-dimethylhexanediamine (DMHD/NO), sodium nitroprusside, intravenous nitroglycerin, and aspirin on acute platelet-thrombus formation under conditions of high-shear blood flow in a rabbit extracor poreal perfusion model. Materials and Methods: Strips of porcine aortic media were perfused in a Badimon cham ber with arterial blood from 20 New Zealand White rabbits for 10 minutes at a shear rate of 1700 s-1. Thrombus formation was quantified by morphometric analysis of thrombus area. Effects on collagen-induced platelet aggregation, blood pressure, bleeding time, and acti vated clotting time were also examined. Results: DMHD/NO inhibited thrombus area and platelet aggregation in a dose-dependent manner with a 90% reduction in thrombus area (0.018 ± 0.039 vs 0.215 ± 0.085 mm 2/mm control, P < .001) and a 50% reduction in platelet aggregation (4.8 ± 4.4 vs 9.9 ± 4.1 Ω con trol, P = .04) at the highest dose of 1.0 nM/kg and 100 μM/L, respectively, without any effects on blood pressure, bleeding time, or activated clotting time. In contrast, equimolar concentrations of sodium nitroprusside and intravenous nitroglycerin had significantly reduced effects on thrombus area compared to DMHD/NO and were associated with signifi cant reductions in blood pressure and prolongation of bleeding time. Aspirin had no effect on thrombus area at 1 μM/kg but reduced thrombus area and prolonged bleeding time at 2 and 5 μM/kg. Conclusions: Local delivery of DMHD/NO produced a 90% inhibition of experimental acute platelet-thrombosis under high-shear flow conditions without producing adverse systemic hemodynamic or hemostatic effects. Thus, inhibition of thrombus formation by local delivery of a rapidly acting NO donor may be an effective strategy for prevention of arterial injury- induced thrombosis.

We studied the effect of arterial balloon injury on nuclear factor-kappaB (NF-kappaB) mobilization and ICAM-1 expression in untreated rats and rats treated with aspirin. Baseline NF-kappaB nuclear binding in smooth muscle cells (SMC) increased two-fold within 6 h after balloon injury. The binding returned to baseline 3 days after injury. Consistently nuclear staining of p65 active subunit increased in the medial SMC following balloon injury. There was no baseline ICAM-1 expression. Within 3 days after balloon injury there was marked medial ICAM-1 expression, that localized to neointima 7 days after injury and to regrowing endothelial cells 14 days after injury. Treatment with aspirin inhibited NF-kappaB nuclear translocation and binding and was associated with reduction of ICAM-1 expression, SMC proliferation and neointimal thickening following balloon injury. These data suggest that transient mobilization of NF-kappaB in vascular SMC after balloon injury mediates ICAM-1 expression and is involved in arterial response to balloon injury.

Congestive heart failure is a burgeoning problem, especially in older adults, affecting nearly 0.1% of subjects >65 years old, accounting for nearly 20% of all hospitalizations in this age group, and costing the healthcare system a bundle.1 Several experimental observations have demonstrated an important role for progressive dilation and geometric remodeling of the left ventricle in worsening cardiac pump function.2 The results of experimental studies on the adverse implications of ventricular dilation and remodeling have been confirmed in clinical and epidemiological studies of depressed ventricular function and congestive heart failure in humans.2,3 Studies of the natural history of left ventricular dysfunction provide evidence to directly implicate left ventricular dilation and remodeling to an adverse clinical outcome in patients with congestive heart failure. Ventricular dilation and remodeling impose an increased mechanical disadvantage to the pump function by increasing wall stress and consequently the hemodynamic load and by contributing to mitral regurgitation and possibly arrhythmogenesis in patients with congestive heart failure independently of the neurohormonal status. Therapeutic trials have also shown that the majority of clinically useful and approved treatment modalities in heart failure attenuate or reverse ventricular dilation and remodeling.4–8 Despite multiple drug therapies, including neurohormonal blockade, progressive ventricular dilation and adverse remodeling frequently continue in many patients with depressed ventricular function. Although orthotopic cardiac transplantation is highly successful in alleviating heart failure and improving survival, limited donor supply, organ rejection, and complications related to immunosuppressive therapy continue to limit the utility of this procedure. In recent years, several new nonpharmacological approaches for attenuation and or reversal of ventricular dilation and remodeling have been introduced, including partial ventricular resection or the Batsita procedure, the endoventricular patch repair or the Dor procedure, and cardiac resynchronization therapy with biventricular pacing.9 The idea for a passive restraining device to …

Arterial calcification in the coronary arteries frequently indicates concomitant atherosclerotic plaque but can be present in the medial layers with no evidence of plaque. Calcification of the medial layer of arteries is seen most often in the peripheral arteries but also is widely recognized In the coronary arteries. We describe 2 patients who had marked medial and intimal calcification of the coronary arteries with little or no accompanying atherosclerosis.

Background It is increasingly evident that CD8+ T cells are involved in atherosclerosis but the specific subtypes have yet to be defined. CD8+CD25+ T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8+CD25+ T cells in experimental atherosclerosis were investigated in this study. Methods and results CD8+CD25+ T cells were observed in atherosclerotic plaques of apoE(−/−) mice fed hypercholesterolemic diet. Characterization by flow cytometric analysis and functional evaluation using a CFSE-based proliferation assays revealed a suppressive phenotype and function of splenic CD8+CD25+ T cells from apoE(−/−) mice. Depletion of CD8+CD25+ from total CD8+ T cells rendered higher cytolytic activity of the remaining CD8+CD25− T cells. Adoptive transfer of CD8+CD25+ T cells into apoE(−/−) mice suppressed the proliferation of splenic CD4+ T cells and significantly reduced atherosclerosis in recipient mice. Conclusions Our study has identified an athero-protective role for CD8+CD25+ T cells in experimental atherosclerosis.

A large body of evidence implicates the immune system in the pathogenesis of atherosclerosis. Both active and passive immunizations have been tested as immunomodulation strategies to confer protective effect against atherogenesis. This review focuses on the current knowledge of the complex role and the potential for immune modulation therapy via active immunization for atherosclerosis.

Background: T cells play an important role in angiotensin II (AngII)-induced hypertension but the specific subtype involved remains unknown. We recently reported that immunization with apoB-100 related peptide p210 modified CD8+ T cell function, and reduced mean blood pressure (BP) and renal inflammation in AngII-infused apoE (-/-) mice. In this study, we assessed the role of CD8+ T cells in p210 vaccine mediated renal protection. Method and Results: ApoE (-/-) mice were immunized with p210/cBSA/Alum (p210; 100 μg) at 7, 10, and 12 weeks of age. Mice receiving PBS or cBSA/Alum (cBSA) served as controls. At 10 weeks of age, mice were subcutaneously implanted with an osmotic pump which released AngII (1 mg/Kg/min), and were euthanized 4 weeks later. Flow cytometric analysis showed p210 treated mice had significantly increased CD8+CD25+IL-12+ splenic T cells indicating CD8+ T cell activation (Table). Renal fibrosis assessed by Masson-Trichrome staining and pro-fibrotic gene expression was significantly reduced in p210 vaccine treated group (Table). P210 immunized mice with CD8+ T cell depletion by a monoclonal antibody (Ab) developed higher mean BP compared to similarly treated mice receiving isotype Ab or no Ab injection ( no Ab injection = 123±1 mmHg, CD8 Ab = 132±1 mmHg*, isotype Ab = 123±2 mmHg, *p Conclusion: CD8+ T cells elicited by an apoB-100 related peptide vaccine mediate protection against AngII-induced hypertension and renal fibrosis.

Background CD 8 + T ‐cell activation, characterized by increased CD 28 expression, reduces neointima formation after arterial injury in mice. The CD 8 + CD 28 hi phenotype is associated with increased effector function. In this study, we used a mouse model that has CD 8 + but no CD 4 + T cells ( CD 4−/−) to assess the role of CD 8 + T cells and test the function of CD 8 + CD 28 hi T cells in modulating neointima formation after arterial injury. Methods and Results Neointima formation after pericarotid arterial cuff injury was significantly less in CD 4−/− mice compared with wild‐type ( WT ) mice. Negligible baseline lytic activity by splenic CD 8 + T cells from uninjured WT mice against target syngeneic smooth muscle cells was significantly increased 7 days after injury. Interestingly, CD 8 + T cells from uninjured CD 4−/− mice had significant lytic activity at baseline that remained elevated 7 days after injury. CD 8 + T ‐cell lytic activity was significantly reduced by depletion of CD 28 hi cells. CD 8 + CD 28 hi T cells adoptively transferred into recipient Rag‐1−/− mice significantly reduced neointima formation compared with CD 8 + CD 28 + T ‐cell recipient mice. Conclusions CD 8 + T cells reduced neointima formation after arterial injury, attributed in part to increased function of the CD 8 + CD 28 hi phenotype.

Background Coronary stenting is limited by subacute thrombosis, especially in smaller-diameter vessels, in which shear rates are high. The objective of the present study was to determine whether local delivery of a new type of NO donor, the NO adduct of N,N′ -dimethylhexanediamine (DMHD/NO), inhibits acute stent thrombosis (ST) at high-shear flow. Methods and Results Effects of local infusion of DMHD/NO, intravenous aspirin, and heparin on ST were evaluated in an ex vivo porcine AV shunt model. Nitinol stents (2 mm in diameter, n=120) were placed in a tubular chamber and perfused with blood from pigs (n=13) at a shear rate of 2100 s −1 for 20 minutes. ST was quantified by measurement of dry thrombus weight (TW). Effects on platelet aggregation (PA), blood pressure, bleeding time, and activated clotting time (ACT) were also examined. There was a dose-dependent inhibition of ST and PA by DMHD/NO. TW was reduced by 95% (1±2 versus 16±4 mg control, mean±SD, P P P =.3). Heparin (200 U/kg) reduced TW by 33% (14±4 versus 21±3 mg control, P Conclusions Local delivery of DMHD/NO produced a 15-fold inhibition of acute ST at high-shear flow without producing adverse systemic hemostatic or hemodynamic effects. Thus, treatment with DMHD/NO may be an effective strategy for prevention of stent thrombosis.

Although the existence of an immune response against modified lipoproteins in atherosclerosis has been observed in experimental animals as well as in humans, the precise pathophysiological relevance of these findings remains unclear. In this study we determined the effect of an immunization with homologous LDL and copper-oxidized LDL on the formation of atherosclerotic plaque in hypercholesterolemic rabbits. Immunizations were performed at the start of a cholesterol-rich diet and 3 weeks later. After 16 weeks, antibodies against oxidized LDL had developed in rabbits given hypercholesterolemic diet alone, but the titers were increased by twofold in rabbits immunized with oxidized LDL as well as in rabbits immunized with LDL, suggesting that the LDL had also become oxidized during the preparation and/or immunization procedure. Immunization with LDL and oxidized LDL reduced atherosclerotic lesions in the proximal aorta by 74% ( P P =NS), respectively. The cellular composition of the lesions was not affected by the immunizations. These results support the hypothesis that an immune response against modified LDL has a protective effect against the development of early atherosclerotic lesions.

Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Atherosclerotic vascular disease is a leading cause of death and disability throughout the USA and other industrialized nations and consumes enormous fiscal resources. Atherosclerosis involves the development of a plaque composed of variable amounts of atherogenic lipoproteins, extracellular matrix (collagen, proteoglycans, glycosaminoglycans), calcium, vascular smooth muscle cells, inflammatory and immune cells (chiefly monocyte-derived macrophages, T lymphocytes, mast cells, dendritic cells), and new blood vessels. Atherosclerosis represents a chronic inflammatory response to vascular injury triggered by a variety of risk factors that injure endothelium and promote lipoprotein infiltration, retention, and modification, combined with leukocyte entry, retention, proliferation, and activation. Atherosclerosis predisposes to arterial thrombosis and acute arterial occlusion when plaque disruption leads to activation of the clotting cascade in the vasculature. Ultimately, most lethal and significant occlusive cardiovascular events result from plaque disruption leading to thrombosis. Disruption of plaques is believed to result from inflammation and immune activation in the plaque leading to matrix degradation and inadequate repair. Inflammation plays a crucial role in the initiation, progression, and eventual destabilization of atherosclerotic plaques. Disruption-prone plaques generally contain large necrotic lipid core with adventitial remodeling, plaque cap inflammation, increased neovascularity, and intraplaque hemorrhage.

The outcome of patients with Thrombolysis in Myocardial Infarction (TIMI) trial grade 2 flow is worse than that of patients with TIMI grade 3 flow after thrombolytic therapy for acute myocardial infarction. It is unclear whether TIMI grade 2 flow represents incomplete recanalization of the culprit lesion or poor distal runoff. The Thrombolytic Trial of Eminase (anistreplase) in Acute Myocardial Infarction (TEAM)-2 and TEAM-3 were randomized trials comparing anistreplase with streptokinase (TEAM-2, n = 370) or with alteplase (tissue plasminogen activator) (TEAM-3, n = 325). We compared the minimal luminal diameter of the culprit lesion in patients with TIMI grade 2 flow with that in patients with TIMI grade 3 flow both 90 minutes (TEAM-2) and 1 day (TEAM-3) after thrombolysis. Patients with TIMI grade 2 flow had a lower residual luminal diameter in the culprit lesion than patients with TIMI grade 3 flow (TEAM-2, 0.58 +/- 0.03 vs 0.79 +/- 0.02 mm, p = 0.0001; TEAM-3, 0.88 +/- 0.04 vs 1.17 +/- 0.03 mm, p = 0.0001, for patients with TIMI grades 2 and 3 flow). Residual percent stenosis was correspondingly higher in patients with TIMI grade 2 flow. At the early angiogram, 66% of patients with TIMI grade 2 flow, but only 35% of those with TIMI grade 3 flow, had a minimal luminal diameter of 0.6 mm (positive predictive value 87%, negative predictive value 35%). Incomplete recanalization of the culprit lesion may thus be an important determinant of TIMI grade 2 flow after thrombolysis. Whether more complete thrombolysis or rescue angioplasty improves outcome in these patients deserves evaluation.

As care and outcomes for acute myocardial infarction (MI) continue to improve, ventricular septal defect (VSD) remains a very serious mechanical complication of acute MI that is associated with high mortality and morbidity. Patients with post-MI VSD are often late presenting acute coronary syndrome

On behalf of my colleagues in the Scientific Program Committee, it is my honor and pleasure to present a few of the highlights among the scientific presentations at the annual Scientific Sessions of the American College of Cardiology, held in March to April 2003, in the category of Myocardial

Inflammatory response is triggered when tissues are exposed to a variety of insults. This response consists of a cascade of events that includes release of various chemical mediators and recruitment of circulating blood cells (platelets and leukocytes) to the site of injury and their subsequent activation. The inflammatory response attempts to contain the damaging effects of the insult, leading to recovery from its injurious effects. However, when normal checkpoints that limit continuing or ongoing inflammation fail, inflammatory response can become a liability that leads to a diverse group of diseases, including atherosclerosis and thrombosis. A large body of evidence has implicated inflammation in the initiation, progression, and destabilization of atherosclerotic vascular disease, linking many of the known risk factors to atherothrombosis.1,2 However, the role of inflammation in other vaso-occlusive disorders, such as neointimal thickening after mechanical injury to arteries during angioplasty and/or stenting, is not as well appreciated. Neointimal thickening after mechanical injury predominantly consists of a fibroproliferative reaction initially involving proliferating smooth muscle cells and later dominated by accumulation of extracellular matrix. Neointimal thickening plays a decisive role in restenosis after stenting because stenting essentially precludes constrictive remodeling, whereas postangioplasty restenosis involves elastic recoil and constrictive or negative vessel wall remodeling (vessel shrinkage) in addition to neointimal thickening. An improved understanding of the molecular mechanisms leading to neointimal thickening after mechanical injury would pave the way for development of novel therapeutic approaches for prevention of restenosis, which has remained the Achilles’ heel of endovascular interventions. See p 2244 Several lines of evidence have suggested that platelet/fibrin deposition and activation of inflammatory genes, followed by increased leukocyte trafficking into the injured vessel wall, may provide a key stimulus for subsequent neointima formation.3–7 Although most experimental studies have identified mononuclear leukocytes (monocyte-macrophage lineage) as the primary inflammatory cell types, …

Background There is an ongoing debate about the performance of non–high-density lipoprotein cholesterol (non-HDL-C) compared with apolipoprotein B (apo B) in the prediction of coronary heart disease (CHD) risk. Therefore, we compared the associations between non-HDL-C and apo B in regard to CHD among apparently healthy Western European individuals. Design In the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk prospective population study, 25 639 men and women aged 45–79 years were followed for 11·4 ± 2·8 years. Those with diabetes or prevalent CHD at baseline were excluded. A total of 2066 (12·1%) participants developed CHD during 195 692 person-years follow-up. Results The multivariable-adjusted hazard ratio [HR] of future CHD per one standard deviation increase was 1·22 [95% confidence interval (CI): 1·17–1·27] for LDL-C, 1·26 (95% CI 1·20–1·31) for non-HDL-C and 1·19 (95% CI 1·14–1·24) for apo B, respectively. The multivariable-adjusted HR of future CHD in the highest quartile LDL-C was 1·67 (95% CI: 1·47–1·91). For non-HDL-C and apo B, these respective HRs were 1·87 (95% CI: 1·62–2·15) and 1·56 (95% CI: 1·36–1·78). Kaplan–Meier survival analyses showed that there was incremental and comparable increase in risk of CHD with increasing quartiles of both non-HDL-C and apo B. Conclusions In this prospective study, non-HDL-C and apo B were comparable in their ability to predict risk of future CHD.

Forkhead box P3 (Foxp3) is well known for its highly restricted expression in T regulatory cells (Tregs). A recent study suggested the existence of a Foxp3 positive macrophage subpopulation in mouse bone marrow, spleen, liver, lymph nodes, and thymus that exhibited immune regulatory effect similar to Tregs. Before this report was retracted, we attempted to study the function of this macrophage subpopulation in a mouse model of hyperlipidemia. Bone marrow and spleen cells isolated from C57BL/6 apo E(-/-) mice were stained with anti-CD11b, anti-F4/80 and anti-Foxp3 and analyzed by flow cytometry. Our results showed that 3.06-8.08% of CD11b(+)F4/80(+) macrophages from bone marrow cells and 0.24-2.21% from splenic were Foxp3-positive. Unexpectedly, unstained or isotype stained controls also showed strong autofluorescence and similar percentages of these cells fell within the same FL1 channel that counted the anti-Foxp3 stained population. Back gating of the autofluorescent population onto a SSC/FSC plot showed that this population of cells had a higher side scatter. The peritoneal macrophages (PMo) exhibited similar autofluorescence. We used qPCR to further evaluate the expression of Foxp3 mRNA in PMo that were treated with M-CSF, M-CSF+IL-4, M-CSF+TGFβ1 or in BMDM treated with TGFβ1 in the presence of anti-CD3 and CD28 antibody co-stimulators. No expression of Foxp3 mRNA was detected in either cell culture systems, whereas robust Foxp3 gene expression was induced in naive CD4+ cells stimulated with TGFβ1. Consistent with these findings, fluorescence microscopy showed no Foxp3 protein expression in PMo, however Foxp3 expression was easily detected in induced Tregs. We conclude that the reported expression of Foxp3 in macrophages is likely an artifact and that a stringent multimodality approach is critical to demonstrate candidate gene expression in any cell type.