Peter Libby

Inflammation in atherosclerosis

Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

BACKGROUND Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. METHODS We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. RESULTS The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. CONCLUSIONS In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)

Molecular Bases of the Acute Coronary Syndromes

The acute coronary syndromes, including unstable angina and acute myocardial infarction, currently constitute a major preoccupation of clinical cardiology. This century has witnessed a remarkable evolution in our clinical concepts of these syndromes. Herrick1 described the survival of patients with acute coronary thrombosis early in the century. The introduction of the ECG led to major clinical advances in the definition of acute myocardial infarction during the first half of this century and furnished the basis of modern coronary care. In the latter half of this century, the advent of coronary arteriography permitted definition in the living patient of coronary stenoses due to atherosclerosis. The introduction of this diagnostic technique allowed the development of rational treatment modalities such as coronary artery bypass surgery and, subsequently, percutaneous transluminal coronary angioplasty. Until recently, it seemed that we had achieved a firm understanding of the pathophysiology of human coronary artery disease and had devised appropriate modes of therapy for its major manifestations. Yet, recent clinical data suggest that we still have much to learn about the pathophysiology of the acute coronary syndromes. Bypass surgery and angioplasty aim to restore blood flow to sites beyond hemodynamically significant stenoses in the coronary arteries. These revascularization therapies effectively relieve angina pectoris in many cases (although often not permanently). Quite naturally, the availability of these modalities led the cardiology community to focus on high-grade coronary stenosis, visible by angiography, as the critical issue in coronary heart disease. Much of the basis of contemporary cardiology and cardiac surgery rests on the axiom: the greater the stenosis, the greater the risk of a clinical event such as myocardial infarction or unstable angina pectoris. However, data emerging from clinical and pathological studies over the past decade have occasioned a reassessment of this central dogma of clinical cardiology.2 First, the …

Progress and challenges in translating the biology of atherosclerosis

Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.

The immune response in atherosclerosis: a double-edged sword

Immune responses participate in every phase of atherosclerosis. There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Although improved treatment of hyperlipidaemia reduces the risk for cardiac and cerebral complications of atherosclerosis, these remain among the most prevalent of diseases and will probably become the most common cause of death globally within 15 years. This Review focuses on the role of immune mechanisms in the formation and activation of atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers for predicting cardiovascular events. We also outline possible future targets for prevention, diagnosis and treatment of atherosclerosis.

Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

To test the hypothesis that nitric oxide (NO) limits endothelial activation, we treated cytokine-stimulated human saphenous vein endothelial cells with several NO donors and assessed their effects on the inducible expression of vascular cell adhesion molecule-1 (VCAM-1). In a concentration-dependent manner, NO inhibited interleukin (IL)-1 alpha-stimulated VCAM-1 expression by 35-55% as determined by cell surface enzyme immunoassays and flow cytometry. This inhibition was paralleled by reduced monocyte adhesion to endothelial monolayers in nonstatic assays, was unaffected by cGMP analogues, and was quantitatively similar after stimulation by either IL-1 alpha, IL-1 beta, IL-4, tumor necrosis factor (TNF alpha), or bacterial lipopolysaccharide. NO also decreased the endothelial expression of other leukocyte adhesion molecules (E-selectin and to a lesser extent, intercellular adhesion molecule-1) and secretable cytokines (IL-6 and IL-8). Inhibition of endogenous NO production by L-N-monomethyl-arginine also induced the expression of VCAM-1, but did not augment cytokine-induced VCAM-1 expression. Nuclear run-on assays, transfection studies using various VCAM-1 promoter reporter gene constructs, and electrophoretic mobility shift assays indicated that NO represses VCAM-1 gene transcription, in part, by inhibiting NF-kappa B. We propose that NOs ability to limit endothelial activation and inhibit monocyte adhesion may contribute to some of its antiatherogenic and antiinflammatory properties within the vessel wall.

Absence of Monocyte Chemoattractant Protein-1 Reduces Atherosclerosis in Low Density Lipoprotein Receptor–Deficient Mice

Recruitment of blood monocytes into the arterial subendothelium is one of the earliest steps in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, is one likely signal involved in this process. To test MCP-1s role in atherogenesis, low density lipoprotein (LDL) receptor-deficient mice were made genetically deficient for MCP-1 and fed a high cholesterol diet. Despite having the same amount of total and fractionated serum cholesterol as LDL receptor-deficient mice with wild-type MCP-1 alleles, LDL receptor/MCP-1-deficient mice had 83% less lipid deposition throughout their aortas. Consistent with MCP-1 s monocyte chemoattractant properties, compound-deficient mice also had fewer macrophages in their aortic walls. Thus, MCP-1 plays a unique and crucial role in the initiation of atherosclerosis and may provide a new therapeutic target in this disorder.

Current Concepts of the Pathogenesis of the Acute Coronary Syndromes

The last decade has witnessed a major reassessment of our perceptions about the acute coronary syndromes. Today, we recognize that thrombosis underlies most acute complications of atherosclerosis, notably unstable angina and acute myocardial infarction. A consensus has emerged that inflammation plays a decisive role in the pathophysiology of these acute thrombotic events (Figure 1). Knowledge of the underlying mechanisms has increased substantially since this topic was last reviewed in these pages 6 years ago. The present article provides an update of this rapidly moving field. Figure 1. Initiation, progression, and complication of human coronary atherosclerotic plaque. Top, Longitudinal section of artery depicting “timeline” of human atherogenesis from normal artery (1) to atheroma that caused clinical manifestations by thrombosis or stenosis (5, 6, 7). Bottom, Cross sections of artery during various stages of atheroma evolution. 1, Normal artery. Note that in human arteries, the intimal layer is much better developed than in most other species. The intima of human arteries contains resident smooth muscle cells often as early as first year of life. 2, Lesion initiation occurs when endothelial cells, activated by risk factors such as hyperlipoproteinemia, express adhesion and chemoattractant molecules that recruit inflammatory leukocytes such as monocytes and T lymphocytes. Extracellular lipid begins to accumulate in intima at this stage. 3, Evolution to fibrofatty stage. Monocytes recruited to artery wall become macrophages and express scavenger receptors that bind modified lipoproteins. Macrophages become lipid-laden foam cells by engulfing modified lipoproteins. Leukocytes and resident vascular wall cells can secrete inflammatory cytokines and growth factors that amplify leukocyte recruitment and cause smooth muscle cell migration and proliferation. 4, As lesion progresses, inflammatory mediators cause expression of tissue factor, a potent procoagulant, and of matrix-degrading proteinases that weaken fibrous cap of plaque. 5, If fibrous cap ruptures at point of weakening, coagulation factors …

The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6Chi and -6Clo monocytes via CCR2 and CX3CR1, respectively. Ly-6Chi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6Clo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6Chi monocytes digest damaged tissue, whereas Ly-6Clo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6Chi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.

Identification of Splenic Reservoir Monocytes and Their Deployment to Inflammatory Sites

Monitoring Monocyte Reservoirs Monocytes are cells of the immune system that are recruited to sites of tissue injury and inflammation where they help to resolve the infection and are important for tissue repair. The bone marrow and blood are believed to be the primary reservoirs from which monocytes are mobilized after injury. Swirski et al. (p. 612; see the Perspective by Jia and Pamer) now demonstrate that the spleen also serves as a critical reservoir of monocytes that are recruited during ischemic myocardial injury. Monocytes in the spleen are very similar in phenotype to blood-derived monocytes and are mobilized to the injured heart, where they represent a large fraction of the total monocytes that are recruited. The chemoattractant, angiotensin II, is required for optimal monocyte mobilization from the spleen and emigration into injured tissue. A rapid deployment force of immune cells is identified in the spleen that is important for resolving inflammation. A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a resource that the body exploits to regulate inflammation.