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Biomedical subjects

Peter Libby

Publications and source records attributed to Peter Libby.

At least 91 records · Page 5Linked to original sources
PubMed2003

Soluble CD40L: risk prediction after acute coronary syndromes.

BACKGROUND: Elevated plasma concentrations of soluble CD40 ligand (sCD40L) indicate increased risk for future cardiovascular events in apparently healthy women. This study tested the hypothesis that plasma sCD40L, alone or in combination with troponin (cTnI) or C-reactive protein (CRP), may identify patients with acute coronary syndromes at heightened risk for recurrent cardiac events. METHODS AND RESULTS: In a nested case-control study (cases, n=195; controls, n=195) within the OPUS-TIMI16 trial, patients with the prespecified study end points death, myocardial infarction (MI), or congestive heart failure (CHF) within 10 months had significantly higher median (25th, 75th percentiles) sCD40L plasma levels than did controls (0.78 [0.34, 1.73] ng/mL versus 0.52 [0.16, 1.42] ng/mL, P<0.002). After adjustment for other risk predictors and levels of cTnI and CRP, sCD40L levels above median were associated with higher risk for death, MI, and the composite death/MI or death/MI/CHF (adjusted hazard ratios, 1.9 [P<0.05], 1.9 [P<0.001], 1.9 [P<0.001], and 1.8 [P<0.01], respectively). Interestingly, patients with elevated plasma levels of sCD40L and cTnI showed a markedly increased risk of death, MI, or death/MI/CHF compared with patients with the lowest levels of both markers (adjusted hazard ratios, 12.1, 7.2, and 4.3, respectively; all P<0.01). CONCLUSIONS: Elevated plasma levels of sCD40L identify patients with acute coronary syndromes at heightened risk of death and recurrent MI independent of other predictive variables, including cTnI and CRP. Notably, combined assessment of sCD40L with cTnI complements prognostic information for death and MI.

Acute Disease↗
PubMed2003

Effect of a cleavage-resistant collagen mutation on left ventricular remodeling.

Matrix metalloproteinase-mediated degradation of type I collagen may play a role in cardiac remodeling after strain or injury. To explore this hypothesis, we used mice homozygous (r/r) for a targeted mutation in Col1a1; these mice synthesize collagen I that resists collagenase cleavage at Gly975-Leu976. A total of 64 r/r and 84 littermate wild-type mice (WT) underwent experimental pressure overload by transverse aortic constriction (TAC) or myocardial infarction (MI). Echocardiographic, hemodynamic, and histological parameters were evaluated up to 12 weeks after TAC or 21 days after MI. At 4 weeks after TAC, collagen levels, wall thickness, and echocardiographic parameters were similar in the 2 groups. At 12 weeks after TAC, r/r mice had smaller LV dimensions (ESD: 2.7+/-0.2 mm WT versus 1.7+/-0.2 mm r/r, P<0.013; EDD: 3.8+/-0.2 mm WT versus 3.1+/-0.1 mm r/r, P<0.013); better fractional shortening (30+/-2% WT versus 46+/-4% r/r; P<0.013); and lower LV/body weight ratios (7.3+/-0.6 WT and 5.1+/-0.5 r/r; P<0.013). Surprisingly, these differences were not accompanied by differences in collagen accumulation, myocyte cross-sectional areas, wall thickness, or microvessel densities. Furthermore, no differences in LV remodeling assessed by echocardiography, fibrosis, or hemodynamic parameters were found between r/r and WT mice after MI. Thus, a mutation that encodes a collagenase cleavage-resistant collagen I does not affect early LV remodeling after TAC or MI, suggesting that collagen cleavage at this site is not the mechanism by which metalloproteinases mediate LV remodeling. Collagen cleavage could, however, have a role in preservation of cardiac function in late remodeling by mechanisms independent of collagen accumulation. We were not able to detect collagen cleavage fragments, and could not, therefore, rule out the possibility of collagen cleavage at additional sites.

Animals↗
PubMed2003

Neutrophil elastase in human atherosclerotic plaques: production by macrophages.

BACKGROUND: Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity. METHODS AND RESULTS: Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1beta, TNF-alpha, or IFN-gamma but released it when stimulated by CD40 ligand, a cytokine found in atheroma. CONCLUSIONS: These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.

Antigens, CD↗
PubMed2003

Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones.

BACKGROUND: Considerable evidence implicates the proinflammatory cytokine CD40 ligand (CD40L) in atherosclerosis and accumulating data link type 1 and 2 diabetes, conditions associated with accelerated atherosclerosis, to inflammation. This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L (sCD40L) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation. METHODS AND RESULTS: Subjects with type 1 (n=49) or type 2 diabetes (n=48) had higher (P<0.001) sCD40L plasma levels (6.56+/-3.27 and 6.67+/-2.90 ng/mL, respectively) compared with age-matched control groups (1.40+/-2.21 and 1.32+/-2.68 ng/mL, respectively). Multiple regression analysis demonstrated a significant (P<0.001) association between plasma sCD40L and type 1 as well as type 2 diabetes, independent of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, body mass index, gender, C-reactive protein, and soluble intracellular adhesion molecule-1. Furthermore, in a pilot study, administration of troglitazone (12 weeks, 600 mg/day), but not placebo, to type 2 diabetics (n=68) significantly (P<0.001) diminished sCD40L plasma levels by 29%. The thiazolidinedione lowered plasma sCD40L in type 2 diabetic patients with long-standing disease (>3 years) with or without macrovascular complications (-34% and -29%, respectively) as well as in type 2 diabetic patients with more recent (<3 years) onset of the disease (-27%; all P<0.05). CONCLUSIONS: This study provides new evidence that individuals with type 1 or 2 diabetes have a proinflammatory state as indicated by elevated levels of plasma sCD40L. Troglitazone treatment of type 2 diabetic patients diminishes sCD40L levels, suggesting a novel antiinflammatory mechanism for limiting diabetes-associated arterial disease.

Acute Disease↗
PubMed2003

Elastogenesis in human arterial disease: a role for macrophages in disordered elastin synthesis.

OBJECTIVE: Elastin, an extracellular matrix protein, constitutes about 30% of the dry weight of the arteries. Elastolysis induced by inflammatory processes is active in chronic arterial diseases. However, elastogenesis in arterial diseases has received little attention. In this work we hypothesized that disordered elastogenesis is active in matrix remodeling in atheroma and abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Human AAA and atheroma have 4- to 6-fold more tropoelastin protein than nondiseased arteries. The smooth muscle cell-containing media and fibrous cap of atherosclerotic arteries contain ordered mature elastin, whereas macrophage (MPhi)-rich regions often have disorganized elastic fibers. Surprisingly, in addition to smooth muscle cells, MPhis in diseased arteries also produce the elastin precursor tropoelastin, as shown by double immunostaining, in situ hybridization, and reverse transcription-polymerase chain reaction for tropoelastin mRNA. Cultured monocyte-derived MPhis can express the elastin gene. AAA have 9-fold but atheroma only 1.6-fold lower levels of desmosine, a marker for mature cross-linked elastin, than normal arteries. CONCLUSIONS: This study demonstrates ongoing but often ineffective elastogenesis in arterial disease and establishes human macrophages as a novel source for this important matrix protein. These results have considerable import for understanding mechanisms of extracellular matrix remodeling in arterial diseases.

Aorta↗
PubMed2003

Mechanisms of plaque stabilization with statins.

The traditional view of cardiovascular disease held that the degree of stenosis defined high-risk lesions and that removal of cholesterol shrank these lesions and thereby enlarged the lumen. Advances in understanding of the pathophysiology of the acute coronary syndromes refute this view. We now appreciate that vascular biology determines plaque stability and that statins stabilize plaque by favorably altering this biology. They do so chiefly (but probably not exclusively) by cholesterol lowering. In addition to reducing the cholesterol content of plaque, lipid lowering inhibits inflammation, and decreases collagenolytic activity and thrombotic potential. The role of lipid-independent effects remains unclear because many studies used statin concentrations too high to have any clinical relevance. However, data suggest that statin-induced alterations in the function of small G proteins may contribute to the anti-inflammatory and antithrombotic actions of statins in clinical practice.

Animals↗
PubMed2003

Vascular biology of atherosclerosis: overview and state of the art.

Our current understanding of the vascular biology of atherogenesis and its clinical manifestations suggests a pathophysiology that is much more complex than mere lipid storage. Recent advances support the current view of atherosclerosis as an inflammatory process that initiates and promotes lesion development to the point of acute thrombotic complications and clinical events. Inflammatory cells localize in early-stage atherosclerotic lesions, and recent basic research has established a causal relation between inflammatory mediators or cytokines, and the steps involved in progressing from local inflammation through plaque formation. Inhibition of the action of certain specific proinflammatory cytokines, such as CD40 ligand, interferes with atherogenesis in mice. Increased circulating levels of inflammatory markers indicate increased cardiovascular risk. Thus, the time has come to embrace inflammation as a common pathway for atherogenic risk factors and for providing new opportunities for therapeutic intervention.

Animals↗
PubMed2003

Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma: an in vivo study with high-resolution MRI.

OBJECTIVE: The CD40/CD40 ligand pathway mediates inflammatory processes important in atherogenesis and the formation of the intraplaque lipid pool. We tested the hypothesis that plasma levels of soluble CD40 ligand are elevated in patients with evidence of a lipid pool on high-resolution magnetic resonance imaging (MRI) of carotid stenoses. METHODS AND RESULTS: We recruited 49 patients with evidence of carotid atherosclerosis on ultrasonography; 3 patients could not undergo carotid MRI because of claustrophobia. The remaining 46 patients underwent high-resolution MRI of the carotid arteries. Two radiologists blinded to all other data determined the presence or absence of an intraplaque lipid pool based on the loss of signal between the 20-ms echo time (TE20) and the fat-suppressed TE55 fast spin-echo images. Plasma levels of soluble CD40 ligand were determined by ELISA. Baseline levels of soluble CD40 ligand were higher among patients with evidence of intraplaque lipid (n=14) than among those without it (n=32; median, 2.54 ng/mL; interquartile range [IQR], 1.85 to 3.52 vs median, 1.58 ng/mL; IQR, 1.21 to 2.39; P=0.02). In contrast, soluble CD40 ligand levels were not correlated with percent diameter stenosis (r=-0.19; P=0.21). The relative risk for intraplaque lipid associated with soluble CD40 ligand levels above the median was 6.0 (95% confidence interval, 1.15 to 31.23; P=0.03). The magnitude of this predictive effect did not substantially change after adjustment for traditional cardiovascular risk factors (relative risk, 5.12; 95% confidence interval, 0.78 to 33.73; P=0.09). CONCLUSIONS: Plasma levels of soluble CD40 ligand may predict patients with features of high-risk atherosclerotic lesions. These data provide novel insight into the mechanism through which elevated levels of soluble CD40 ligand may reflect cardiovascular risk in humans and illustrate the potential value of interfacing high-resolution MRI with studies of vascular inflammation.

Aged↗
PubMed2003

Effects of statins in reducing thrombotic risk and modulating plaque vulnerability.

A large body of evidence demonstrates that statin therapy reduces risk for coronary events. This benefit probably stems in large part from lipid lowering, but lipid-independent cellular effects may also contribute. Statin therapy may lower the risk of thrombosis by reducing tissue factor expression and increasing plasminogen activators while reducing plasminogen-activator inhibitor. The statins may also improve endothelial function and reduce inflammatory response by increasing nitric oxide activity; all statins tested can decrease levels of C-reactive protein, a systemic marker of inflammation. Indeed, limiting inflammation may prove an important mechanism of statins' clinical benefits due to both lipid lowering and direct cellular effects. For example, attenuation of inflammation probably promotes maintained integrity of the fibrous cap of the atherosclerotic lesion by inhibiting processes that degrade the collagenous structure of the cap. Rupture of the fibrous cap causes most fatal coronary thrombosis.

Animals↗
PubMed2003

Tumor necrosis factor receptor -1 and -2 double deficiency reduces graft arterial disease in murine cardiac allografts.

Graft arterial disease (GAD) remains the leading cause of long-term solid organ allograft failure. Tumor necrosis factor (TNF) promotes multiple aspects of allograft rejection via binding to type 1 (p55) and type 2 (p75) receptors. We used TNF type 1 receptor deficient (TNFR1KO), type 2 receptor deficient (TNFR2KO) and receptor double-deficient (TNFRDKO) mice to assess the relative roles of TNFR in acute rejection and GAD. Heterotopic cardiac transplantation was performed between C57BL/6 (B/6) and Balb/c (B/c) mice (total allomismatches) to assess the effects on graft survival; B/6 and Bm12 mice (class II mismatches) were used to assess the effects on GAD 8 weeks after transplantation. We found that graft survival in the total allomismatch combinations was the same regardless of TNFR status. In class II mismatches, wild-type (WT) combinations showed severe GAD, and GAD was not diminished when WT hearts were transplanted into TNFRDKO hosts. TNFR1KO donors or TNFR2KO donors had GAD comparable to WT donors, however, GAD was significantly diminished in B/6 TNFRDKO donor hearts. We conclude that both p55 and p75 signals on donor vascular wall cells are involved in the development of GAD, and either TNFR is capable of mediating a response that will culminate in GAD.

Animals↗
PubMed2003

Macrophage migration inhibitory factor is associated with aneurysmal expansion.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine released mainly from macrophages and activated lymphocytes. Both atherosclerosis and abdominal aortic aneurysm (AAA) are inflammatory diseases tightly linked to the function of these cells. The correlation and contribution of MIF to these human diseases remain unknown, although a recent rabbit study showed expression of this cytokine in atherosclerotic lesions. MATERIAL AND METHODS: MIF immunohistochemistry was performed on tissue sections from five normal aortas, seven atherosclerotic carotids, and six AAAs. A group of 112 men with small AAAs (defined as 3 to 5 cm) was recruited at the time of diagnosis, had serum samples taken, and was followed annually for 1 to 5 years (mean, 2.9 years) and referred for surgery if the AAA exceeded 5 cm in diameter. Of this study group, 98 had serum MIF measured with an enzyme-linked immunosorbent assay and 61 had detectable levels. RESULTS: In human atherosclerotic and aneurysmal lesions, MIF protein colocalized in macrophages, endothelial cells, and smooth muscle cells, but normal arteries had negligible MIF expression. Furthermore, serum-MIF levels correlated significantly with annual expansion rate (r = 0.28; P =.005), persisting after adjustment for initial AAA size, smoking habits, diastolic blood pressure, ankle blood pressure index, and age. After exclusion of 38 cases with MIF levels below the detection limit, initial AAA size was also significantly correlated with the MIF levels (r = 0.42; P =.001), persisting after adjustment for similar confounders, and the correlation coefficient with expansion rate increased to 0.42 (P =.001). CONCLUSION: Highly expressed MIF in macrophages, endothelial cells, and smooth muscle cells in lesions from atherosclerosis and AAA and significant association between serum MIF level and AAA initial size and AAA expansion rate in a group of patients with AAA suggest a potential involvement of this proinflammatory cytokine in the pathogenesis of these cardiovascular diseases.

Aged↗
PubMed2003

Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice.

Human atherosclerotic lesions overexpress the lysosomal cysteine protease cathepsin S (Cat S), one of the most potent mammalian elastases known. In contrast, atheromata have low levels of the endogenous Cat S inhibitor cystatin C compared with normal arteries, suggesting involvement of this protease in atherogenesis. The present study tested this hypothesis directly by crossing Cat S-deficient (CatS(-/-)) mice with LDL receptor-deficient (LDLR(-/-)) mice that develop atherosclerosis on a high-cholesterol diet. Compared with LDLR(-/-) mice, double-knockout mice (CatS(-/-)LDLR(-/-)) developed significantly less atherosclerosis, as indicated by plaque size (plaque area and intimal thickening) and stage of development. These mice also had markedly reduced content of intimal macrophages, lipids, smooth muscle cells, collagen, CD4(+) T lymphocytes, and levels of IFN-gamma. CatS(-/-)LDLR(-/-) monocytes showed impaired subendothelial basement membrane transmigration, and aortas from CatS(-/-)LDLR(-/-) mice had preserved elastic laminae. These findings establish a pivotal role for Cat S in atherogenesis.

Animals↗
PubMed2002

Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease.

Recent appreciation of atherosclerosis as a chronic, inflammatory disease has rekindled efforts to examine the role that infectious agents may play in atherogenesis. In particular, much interest has focused on infection with Chlamydia pneumoniae. The possibility that a prokaryote contributes to atherogenesis has high clinical interest, as C pneumoniae infection may be a treatable risk factor. To review the evidence implicating C pneumoniae in the pathogenesis of atherosclerosis, we searched MEDLINE for articles published between January 1966 and October 2002 on the association of C pneumoniae and atherosclerosis. We also used online resources, texts, meeting abstracts, and expert opinion. We included 5 types of studies (epidemiological, pathology based, animal model, cell biology, and human antibiotic treatment trials) and extracted diagnostic, pathophysiologic, and therapeutic information from the selected literature; consensus was reached on interpretation discrepancies. Chlamydia pneumoniae is associated with atherosclerosis by epidemiological and pathology-based studies. Animal model and cell biology studies suggest that the pathogen can modulate atheroma biology, including lipid- and inflammatory-related processes. Although some preliminary antibiotic treatment trials in patients with coronary artery disease indicated a reduction in recurrent coronary events, larger studies have not shown benefits in individuals with stable coronary artery disease. It is unlikely that C pneumoniae infection is necessary to initiate atherosclerosis. Furthermore, conventional antibiotic therapy may not eradicate the organism or reduce mortality in individuals with atherosclerotic vascular disease. Nevertheless, the current body of evidence establishes this pathogen as a plausible, potentially modifiable risk factor in cardiovascular disease.

Animals↗
PubMed2002

Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells.

BACKGROUND: Although CD40 signaling participates in atherosclerosis, links between lipid risk factors and this inflammatory pathway remain obscure. Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation. Therefore, this study analyzed whether oxidized low-density lipoprotein (oxLDL) induces CD40/CD40L expression on cells implicated in atherogenesis and whether statins affect their expression in vitro as well as the expression of soluble CD40L (sCD40L) in vivo. METHODS AND RESULTS: Treatment of human vascular endothelial and smooth muscle cells and mononuclear phagocytes with oxLDL augmented the basal expression of CD40 and CD40L mRNA and protein. In contrast, cerivastatin, atorvastatin, or simvastatin concentration-dependently diminished the constitutive as well as oxLDL- or cytokine-induced expression of the receptor/ligand dyad, an effect reversed by mevalonate. Patients treated with statins had diminished sCD40L plasma levels compared with untreated control patients (8.3+/-3.1 ng/mL [n=11] versus 13.1+/-2.5 ng/mL [n=16], P<0.05), supporting the clinical relevance of the in vitro observations. Platelet-enriched plasma of mice deficient in CD40L showed markedly delayed fibrin clot formation, suggesting a role for the ligand in blood coagulation and supporting the hypothesis that statin-mediated reduction in CD40/CD40L expression might limit thrombosis. CONCLUSIONS: OxLDL may promote expression of CD40 and CD40L in human atheroma. Statins may limit the expression of the CD40 receptor/ligand dyad in two ways, directly as well as through diminished lipoprotein levels. Thus, reduced CD40 signaling may account for some of the statins' antiinflammatory action.

Animals↗