Search PubMed⌕ Search

Biomedical subjects

Peter Libby

Publications and source records attributed to Peter Libby.

At least 55 records · Page 3Linked to original sources
PubMed2005

Characterization of human atherosclerotic plaques by intravascular magnetic resonance imaging.

BACKGROUND: Development and validation of novel imaging modalities to assess the composition of human atherosclerotic plaques will improve the understanding of atheroma evolution and could facilitate evaluation of therapeutic strategies for plaque modification. Surface MRI can characterize tissue content of carotid but not deeper arteries. This study evaluated the usefulness of intravascular MRI (IVMRI) to discern the composition of human iliac arteries in vivo. METHODS AND RESULTS: Initial studies validated IVMRI against histopathology of human atherosclerotic arteries ex vivo. A 0.030-inch-diameter IVMRI detector coil was advanced into isolated human aortoiliac arteries and coupled to a 1.5-T scanner. Information from combined T1-, moderate T2-, and proton-density-weighted images differentiated lipid, fibrous, and calcified components with favorable sensitivity and specificity and allowed accurate quantification of plaque size. The validated approach was then applied to image iliac arteries of 25 human subjects in vivo, and results were compared with those of intravascular ultrasound (IVUS). IVMRI readily visualized inner and outer plaque boundaries in all arteries, even those with extensive calcification that precluded IVUS interpretation. It also revealed the expected heterogeneity of atherosclerotic plaque content that was noted during ex vivo validation. Again, IVUS did not disclose this heterogeneity. The level of interobserver and intraobserver agreement in the interpretation of plaque composition was high for IVMRI but poor for IVUS. CONCLUSIONS: IVMRI can reliably identify plaque composition and size in arteries deep within the body. Identification of plaque components by IVMRI in vivo has important implications for the understanding and modification of human atherosclerosis.

Adult↗
PubMed2005

Associations between soluble CD40 ligand, atherosclerosis risk factors, and subclinical atherosclerosis: results from the Dallas Heart Study.

OBJECTIVE: The purpose of this study was to evaluate the associations between plasma levels of soluble CD40 ligand (sCD40L), atherosclerosis risk factors, and evidence of subclinical atherosclerosis. METHODS AND RESULTS: Plasma levels of sCD40L were measured in 2811 subjects from the Dallas Heart Study, a multiethnic population-based cross-sectional study. Electron Beam Computed Tomography measurements of coronary artery calcium (CAC) and MRI measurements of aortic plaque were performed in 2198 and 1965 subjects, respectively. No association was observed between quartiles of sCD40L and age, sex, race, body mass index, diabetes, smoking, creatinine clearance, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or C-reactive protein. In contrast, weak but statistically significant associations were observed between sCD40L and total cholesterol and triglycerides. The prevalence of detectable CAC (CAC score > or =10) and aortic plaque did not differ across sCD40L quartiles, and individuals with CAC scores <10, > or =10 to 100, >100 to 400, and >400 had similar sCD40L levels. CONCLUSIONS: In a large and representative multiethnic population-based sample, sCD40L was not associated with most atherosclerotic risk factors or with subclinical atherosclerosis. These findings suggest that sCD40L will not be useful as a tool to screen for the presence of subclinical atherosclerosis in the population. Further evaluation of this biomarker should focus on settings in which platelet activation is common, such as following acute coronary syndromes or coronary revascularization procedures.

Adult↗
PubMed2005

Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment.

BACKGROUND: It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB4), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB(4) signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown. METHODS AND RESULTS: To directly assess the role of the LTB4-BLT1 pathway in atherogenesis, we bred BLT1(-/-) mice into the atherosclerosis-susceptible apoE(-/-) strain. Compound-deficient apoE(-/-)/Blt1(-/-) mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE(-/-) controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1(+/+) SMCs and absent in Blt1(-/-) cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions. CONCLUSIONS: These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.

Animals↗
PubMed2005

Pathophysiology of coronary artery disease.

During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a "solid-state" stimulus to thrombosis. Alterations in circulating prothrombotic or antifibrinolytic mediators in the "fluid phase" of the blood can also predispose toward ACS. Recent results have established the multiplicity of "high-risk" plaques and the widespread nature of inflammation in patients prone to develop ACS. These findings challenge our traditional view of coronary atherosclerosis as a segmental or localized disease. Thus, treatment of ACS should involve 2 overlapping phases: first, addressing the culprit lesion, and second, aiming at rapid "stabilization" of other plaques that may produce recurrent events. The concept of "interventional cardiology" must expand beyond mechanical revascularization to embrace preventive interventions that forestall future events.

Constriction, Pathologic↗
PubMed2005

Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells.

The cysteine protease cathepsin L is one of the most potent mammalian elastases and collagenases, widely expressed at basal levels in most tested tissues and cell types, and regulated by pro-inflammatory stimuli. The inflammatory arterial diseases abdominal aortic aneurysm (AAA) and atherosclerosis involve extensive vascular remodeling that requires elastolysis and collagenolysis. This study examined the hypothesis that cathepsin L is over-expressed in human AAA and atherosclerotic lesions and its expression in vascular cell types found in these lesions is regulated by pro-inflammatory cytokines. Immunohistochemical and tissue extract immunoblot analysis demonstrated increased expression of cathepsin L in human AAA and atheromata and localized its expression to lesional smooth muscle cells (SMC), endothelial cells (EC), and macrophages. In primary cultured human SMC, EC, and monocyte-derived macrophages, pro-inflammatory cytokines or growth factors induced the expression of cathepsin L and its activity against extracellular collagen and elastin. Patients with coronary artery stenosis (n=65) had higher serum cathepsin L levels than those without lesions detectable by quantitative coronary angiography (n=30) (1.47+/-0.33 ng/ml versus 0.60+/-0.06 ng/ml, p<0.02). A strong correlation between the percent of stenosis of left anterior descending coronary artery and serum cathepsin L levels in patients with stenosis (R=0.542, p<0.0001), also suggests involvement of cathepsin L in these vascular diseases.

Animals↗
PubMed2005

CADASIL mutations impair Notch3 glycosylation by Fringe.

Mutations in the NOTCH3 gene trigger adult-onset stroke and vascular dementia in patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). All CADASIL mutations described to date affect the epidermal growth factor-like (EGF-like) repeats located in the extracellular domain of the Notch3 receptor. These domains are also the target of sequential complex O-linked glycosylation mediated by protein O-fucosyltransferase 1 and Fringe. We investigated whether O-fucosylation or Fringe-mediated elongation of O-fucose on Notch3 is impaired by CADASIL mutations. Biochemical studies of a Notch3 fragment containing the first five EGF-like repeats of Notch3, including the mutational hot spot, showed that CADASIL mutations do not affect the addition of O-fucose but do impair carbohydrate chain elongation by Fringe. CADASIL changes also induced aberrant homodimerization of mutant Notch3 fragments and heterodimerization of mutant Notch3 with Lunatic Fringe itself. Together, these data suggest that Fringe plays a role in CADASIL pathophysiology.

Animals↗
PubMed2005

Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells.

OBJECTIVE: Recent research suggests a central role for CD40 ligand (CD40L) in atherogenesis. However, the relevant cellular source of this proinflammatory cytokine remains unknown. To test the hypothesis that CD40L expressed on hematopoietic cell types (eg, macrophages, lymphocytes, platelets) is crucial to atherogenesis, we performed bone marrow reconstitution experiments using low-density receptor-deficient (ldlr-/-) and ldlr-/-/cd40l-/- compound-mutant mice. METHODS AND RESULTS: As expected, systemic lack of CD40L in hypercholesterolemic ldlr-/- mice significantly reduced the development of atherosclerotic lesions in the aortic arch, aortic root, and abdominal aorta compared with ldlr-/- mice. Furthermore, atheromata in ldlr-/-/cd40l-/- mice showed reduced accumulation of macrophages and lipids and increased content in smooth muscle cells and collagen compared with ldlr-/- mice. Surprisingly, reconstitution of irradiated ldlr-/- mice with ldlr-/-/cd40l-/- bone marrow did not affect the size or composition of atherosclerotic lesions in the root or arch of hypercholesterolemic ldlr-/- mice. Moreover, lipid deposition in the abdominal aorta diminished only marginally compared with mouse aortas reconstituted with ldlr-/- bone marrow. CONCLUSIONS: These experiments demonstrate that CD40L modulates atherogenesis, at least in mice, primarily by its expression on nonhematopoietic cell types rather than monocytes, T lymphocytes, or platelets, a surprising finding with important pathophysiologic and therapeutic implications.

Animals↗
PubMed2005

Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice.

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves substantial proteolysis of the arterial extracellular matrix. The lysosomal cysteine proteases can exert potent elastolytic and collagenolytic activity. Human atherosclerotic plaques have increased cysteine protease content and decreased levels of the endogenous inhibitor cystatin C, suggesting an imbalance that would favor matrix degradation in the arterial wall. This study tested directly the hypothesis that impaired expression of cystatin C alters arterial structure. Cystatin C-deficient mice (Cyst C-/-) were crossbred with apolipoprotein E-deficient mice (ApoE-/-) to generate cystatin C and apolipoprotein E-double deficient mice (Cyst C-/-ApoE-/-). After 12 weeks on an atherogenic diet, cystatin C deficiency yielded significantly increased tunica media elastic lamina fragmentation, decreased medial size, and increased smooth muscle cell and collagen content in aortic lesions of ApoE-/- mice. Cyst C-/-ApoE-/- mice also showed dilated thoracic and abdominal aortae compared with control ApoE-/- mice, although atheroma lesion size, intimal macrophage accumulation, and lipid core size did not differ between these mice. These findings demonstrate directly the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during experimental atherogenesis.

Animals↗
PubMed2005

Local cytokine environments drive aneurysm formation in allografted aortas.

The mechanistic differences between the pathways that induce stenotic vs. aneurysmal manifestations of atherosclerosis remain unknown. In a murine aortic interposition graft model, T helper cell type 1 (Th1)- vs. Th2-slanted cytokine environments differentially affected the vascular pathology; specifically, blockade of interferon-gamma signaling and/or Th2-enriched environments induced aneurysm formation associated with elastic tissue fragmentation. A Th2 cytokine milieu was shown to increase selected matrix metalloproteinase (MMP) expression, and interleukin 4 stimulated macrophage production of elastolytic matrix metalloproteinase 12 in vitro. The new findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling, and have important implications for the pathophysiology of abdominal aortic aneurysms as well as atherosclerosis.

Animals↗
PubMed2005

Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products.

The pro-inflammatory CD40/CD40L dyad participates in atherogenesis. Plasma levels of the soluble ligand (sCD40L) predict cardiovascular events and are elevated in diabetic patients. This study compared CD40/CD40L surface expression on platelets and T lymphocytes of diabetic and control subjects, and tested whether glucose and advanced glycation end products (AGEs) stimulate sCD40L release. Constitutive and inducible surface expression of CD40/CD40L on platelets or T lymphocytes did not differ between diabetic patients (n = 9) and controls (n = 13). Platelets from diabetic patients contained higher intracellular CD40L than controls (p < 0.05) and thrombin stimulated greater platelet sCD40L release in diabetic patients (15.11 +/- 16.77 ng/ml) compared to controls (3.64 +/- 2.03 ng/ml; p < 0.05). Glucose and AGEs induced platelet sCD40L release and CD40L expression in mouse megakaryocytes. This study demonstrates elevated CD40L content and inducible release from platelets of diabetic patients, and identifies glucose and AGEs as potential triggers of expression and release accounting for the elevated sCD40L plasma levels in these patients.

Animals↗
PubMed2004

Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.

CONTEXT: The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. OBJECTIVE: To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). INTERVENTIONS: Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. MAIN OUTCOME MEASURES: The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. RESULTS: Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. CONCLUSIONS: Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.

Adult↗
PubMed2004

Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques.

BACKGROUND: We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques. METHODS AND RESULTS: To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE-/-) that express collagenase-resistant collagen-I (ColR/R/apoE-/-, n=12) or wild-type collagen-expressing mice (Col+/+/apoE-/-, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from ColR/R/apoE-/- mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of ColR/R/apoE-/- mice contained significantly more intimal collagen than did those of Col+/+/apoE-/- mice. CONCLUSIONS: These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.

Amino Acid Substitution↗
PubMed2004

Wild-type but not interferon-gamma-deficient T cells induce graft arterial disease in the absence of B cells.

OBJECTIVE: Interferon-gamma (IFN-gamma), a cytokine produced primarily by T cells and by activated macrophages, plays a central role in the pathogenesis of graft arterial disease (GAD). This study investigated whether T cells can induce GAD in the absence of humoral alloresponses and whether activated macrophages or other host cell types can substitute as sources of IFN-gamma in GAD. METHODS: Wild-type (WT), IFN-gamma-/-, or recombination-activating-gene-1-/- (RAG-1-/-; lacking mature T and B cells) mice received MHC II-disparate hearts. The grafts were harvested 8 weeks post-transplant and histological and immunohistochemical analyses, RNase protection assay (RPA), and flow cytometry were used to evaluate GAD lesions, infiltrating cell populations, and IFN-gamma expression by infiltrating cells. RESULTS: Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN-gamma expression by both infiltrating T cells and macrophages. No GAD developed in IFN-gamma-/- or in RAG-1-/- hosts, nor was any IFN-gamma expression evident. RAG-1-/- hosts receiving naïve WT or IFN-gamma-/- T cells (10(7)) after heart transplantation demonstrated no mature B cells but showed persistence of transferred T cells up to 8 weeks post-transplant. In the complete absence of B cells and alloantibody, transfer of WT T cells into RAG-1-/- recipients yielded GAD, with associated IFN-gamma expression by the transferred T cells and the host macrophages. Transfer of IFN-gamma-/- T cells induced neither GAD nor host macrophage IFN-gamma expression. CONCLUSIONS: T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN-gamma plays a critical role in GAD pathogenesis.

Adoptive Transfer↗
PubMed2004

Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study.

BACKGROUND: Patients with acute coronary syndromes have elevated plasma levels of the proinflammatory, prothrombotic cytokine CD40 ligand (sCD40L). Statins inhibit CD40L signaling in vitro, but there are no prospective studies of statins and sCD40L in acute coronary syndromes. METHODS AND RESULTS: We measured sCD40L in subjects with an acute coronary syndrome enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects were randomized in this double-blind trial to atorvastatin 80 mg/d or placebo for 16 weeks. Plasma CD40L was measured from 2908 (94%) of 3086 subjects at baseline and 2352 (76%) at 16 weeks. Odds ratios (ORs) and 95% CIs from logistic regression models assessed the risk of recurrent cardiovascular events over 16 weeks (death, nonfatal myocardial infarction, cardiac arrest, and worsening angina requiring rehospitalization) in the placebo group from baseline sCD40L and the effect of atorvastatin on the risk associated with CD40L in all subjects. The effects of atorvastatin on plasma concentrations of CD40L were assessed by Wilcoxon tests. There was a threshold effect, with only high sCD40L (>90th centile) being a risk factor for a recurrent cardiovascular event (OR 1.86, 95% CI 1.25 to 2.77). This risk was abolished by atorvastatin (OR 1.09, 95% CI 0.69 to 1.76), which reduced the risk by 48%. Atorvastatin had only a modest effect on sCD40L (P=0.08). CONCLUSIONS: In patients with acute coronary syndromes, atorvastatin abrogated the risk of recurrent cardiovascular events associated with high sCD40L. Early statin therapy after acute coronary syndromes counters the risk associated with elevated sCD40L.

Aged↗