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Kevin D O'Brien

Publications and source records attributed to Kevin D O'Brien.

33 records · Page 2Linked to original sources
PubMed2004

Increase in serum amyloid a evoked by dietary cholesterol is associated with increased atherosclerosis in mice.

BACKGROUND: Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk. SAA levels can be increased by dietary fat and cholesterol. Moreover, SAA can cause lipoproteins to bind extracellular vascular proteoglycans, a process that is critical in atherogenesis. Therefore, we hypothesized that diet-induced increases in SAA would increase atherosclerosis independent of their effect on plasma cholesterol levels. METHODS AND RESULTS: Female LDL-receptor-null (LDLR-/-) mice were fed high-saturated fat diets (21%, wt/wt), with or without added cholesterol (0.15%, wt/wt), for 10 weeks. Compared with chow-fed controls, the high-fat diets increased plasma SAA levels. Addition of cholesterol further increased SAA levels 2-fold (P<0.05) without further increasing plasma cholesterol levels. Addition of dietary cholesterol also increased atherosclerosis (P<0.05). Four lines of evidence suggest that SAA actually might cause atherosclerosis: (1) SAA levels when mice were euthanized correlated with the extent of atherosclerosis (r=0.49; P<0.02); (2) SAA levels after 5 weeks of diet correlated with the extent of atherosclerosis at 10 weeks (r=0.66; P<0.01); (3) binding of HDL from these animals to proteoglycans in vitro was related to the HDL-SAA content (r=0.65; P<0.01); and (4) immunoreactive SAA was present in lesion areas enriched with both proteoglycans and apolipoprotein A-I, the major HDL apolipoprotein. CONCLUSIONS: Addition of cholesterol to a high-fat diet increased plasma SAA levels and atherosclerosis independent of an adverse effect on plasma lipoproteins, consistent with the hypothesis that SAA may promote atherosclerosis directly by mediating retention of SAA-enriched HDL to vascular proteoglycans.

Animals↗
PubMed2004

Hemorrhage in the atherosclerotic carotid plaque: a high-resolution MRI study.

BACKGROUND AND PURPOSE: High-resolution, multicontrast magnetic resonance imaging (MRI) has developed into an effective tool for the identification of carotid atherosclerotic plaque components, such as necrotic core, fibrous matrix, and hemorrhage/thrombus. Factors that may lead to plaque instability are lipid content, thin fibrous cap, and intraplaque hemorrhage. Determining the age of intraplaque hemorrhage can give insight to the history and current condition of the biologically active plaque. The aim of this study was to develop criteria for the identification of the stages of intraplaque hemorrhage using high-resolution MRI. METHODS: Twenty-seven patients, scheduled for carotid endarterectomy (CEA), were imaged on a 1.5-T GE SIGNA scanner (sequences: 3-dimensional time of flight, double-inversion recovery, T1-weighted (T1W), PDW and T2W). Two readers, blinded to histology, reviewed MR images and grouped hemorrhage into fresh, recent, and old categories using a modified cerebral hemorrhage criteria. The CEA specimens were serially sectioned and graded as to presence and stage of hemorrhage. RESULTS: Hemorrhage was histologically identified and staged in 145/189 (77%) of carotid artery plaque locations. MRI detected intraplaque hemorrhage with high sensitivity (90%) but moderate specificity (74%). Moderate agreement in classifying stages occurred between MRI and histology (Cohen kappa=0.7, 95% CI: 0.5 to 0.8 for reviewer 1 and 0.4, 95% CI: 0.2 to 0.6 for reviewer 2), with moderate agreement between the 2 MRI readers (kappa=0.4, 95% CI: 0.3 to 0.6). CONCLUSIONS: Multicontrast MRI can detect and classify carotid intraplaque hemorrhage with high sensitivity and moderate specificity.

Aged↗
PubMed2004

Smooth muscle cell biglycan overexpression results in increased lipoprotein retention on extracellular matrix: implications for the retention of lipoproteins in atherosclerosis.

Lipoprotein retention on extracellular matrix (ECM) may play a central role in atherogenesis, and a specific extracellular matrix proteoglycan, biglycan, has been implicated in lipoprotein retention in human atherosclerosis. To test whether increased cellular biglycan expression results in increased retention of lipoproteins on ECM, rat aortic smooth muscle cells (SMCs) were transduced with a human biglycan cDNA-containing retroviral vector (LBSN) or with an empty retroviral vector (LXSN). To assess the importance of biglycan's glycosaminoglycan side chains in lipoprotein retention, ECM binding studies were also performed using RASMCs transduced with a retroviral vector encoding for a mutant, glycosaminoglycan-deficient biglycan (LBmutSN). Human biglycan mRNA and protein were confirmed in LBSN and LBmutSN RASMCs by Northern and Western blot analyses. HDL3+E binding to SMC ECM was increased significantly (as determined by 95% confidence intervals for binding curves) for LBSN as compared to either LXSN or LBmutSN cells; the increases for LBSN cell ECM were due primarily to an approximately 50% increase in binding sites (increased Bmax) versus LXSN cell ECM and of approximately 25% versus LBmutSN cell ECM. These results are consistent with the hypothesis that biglycan, through its glycosaminoglycan side chains, may mediate lipoprotein retention on atherosclerotic plaque ECM.

Animals↗
PubMed2004

Hemodynamic effects of the angiotensin-converting enzyme inhibitor, ramipril, in patients with mild to moderate aortic stenosis and preserved left ventricular function.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in patients with aortic stenosis (AS). We determined the hemodynamic effects of ACE inhibitors in patients with mild to moderate aortic stenosis (AS) and preserved left ventricular function. METHODS: Thirteen elderly patients (mean [SD] age = 65 [17] years), with mild to moderate AS (aortic jet velocity 2.5-4.0 m/s), normal left ventricular and renal function, and no clinical coronary artery disease, were enrolled in a single-center, open-label trial comparing the hemodynamic effects at baseline and following titration of ramipril to a maximum dose of 7.5 mg twice daily. Patients were identified from echocardiography laboratory logs. Despite a presumed contraindication to ACE inhibitor use in AS patients, 30% (71 of 235) of patients otherwise meeting inclusion or exclusion criteria were excluded owing to current ACE inhibitor use. Patients were monitored with weekly clinic visits, biweekly laboratory tests, and monthly echocardiograms. RESULTS: There were no significant changes from baseline to week 8 in echocardiographic parameters, including mean (SD) aortic jet velocity [2.9 (0.4) vs 2.9 (0.4) m/s], calculated aortic transvalvular gradient [18 (6) vs 18 (6) mm Hg], or cardiac output [5.5 (1.2) vs 6.0 (2.1) L/min], or significant changes in blood pressure or heart rate. Early discontinuations were for asymptomatic low blood pressure (one patient) or a reversible creatinine increase of 0.3 mg/dL (one patient). CONCLUSIONS: Short-term treatment with up to 7.5 mg twice daily of ramipril was well tolerated in patients with mild to moderate AS and preserved left ventricular function. A surprisingly high proportion of patients with documented AS were already receiving ACE inhibitors.

Adult↗
PubMed2003

Fibrillar amyloid protein present in atheroma activates CD36 signal transduction.

The self-association of proteins to form amyloid fibrils has been implicated in the pathogenesis of a number of diseases including Alzheimer's, Parkinson's, and Creutzfeldt-Jakob diseases. We recently reported that the myeloid scavenger receptor CD36 initiates a signaling cascade upon binding to fibrillar beta-amyloid that stimulates recruitment of microglia in the brain and production of inflammatory mediators. This receptor plays a key role in the pathogenesis of atherosclerosis, prompting us to evaluate whether fibrillar proteins were present in atherosclerotic lesions that could initiate signaling via CD36. We show that apolipoprotein C-II, a component of very low and high density lipoproteins, readily forms amyloid fibrils that initiate macrophage inflammatory responses including reactive oxygen production and tumor necrosis factor alpha expression. Using macrophages derived from wild type and Cd36(-/-) mice to distinguish CD36-specific events, we show that fibrillar apolipoprotein C-II activates a signaling cascade downstream of this receptor that includes Lyn and p44/42 MAPKs. Interruption of this signaling pathway through targeted deletion of Cd36 or blocking of p44/42 MAPK activation inhibits macrophage tumor necrosis factor alpha gene expression. Finally, we demonstrate that apolipoprotein C-II in human atheroma co-localizes to regions positive for markers of amyloid and macrophage accumulation. Together, these data characterize a CD36-dependent signaling cascade initiated by fibrillar amyloid species that may promote atherogenesis.

Amyloid↗
PubMed2003

Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis.

This study was undertaken to determine whether aortic valve calcium (AVC) scores measured by electron beam tomography can identify patients with echocardiographically defined aortic stenosis. Electron beam tomography is increasingly being used to detect coronary artery calcium. AVC can also be measured on electron beam tomographic (EBT) scans obtained to screen for coronary calcium. Whether EBT AVC scores correlate with the presence of aortic stenosis, as assessed by echocardiography, is unknown. Results of this study suggest that AVC scores should be calculated routinely for coronary calcium screening EBT scans, and that patients with Agatston AVC scores above a certain level (e.g., >150) should be referred for echocardiography.

Aortic Valve↗
PubMed2003

Cell-associated and extracellular phospholipid transfer protein in human coronary atherosclerosis.

BACKGROUND: Phospholipid transfer protein (PLTP) plays an important role in HDL particle metabolism and may modulate hepatic secretion of apolipoprotein B-containing lipoproteins. However, whether PLTP might participate directly in human atherosclerotic lesion formation is unknown. METHODS AND RESULTS: The cellular and extracellular distributions of PLTP were determined in normal and atherosclerotic human coronary lesions with a monoclonal antibody to human PLTP. Cell types (smooth muscle cells [SMCs] or macrophages), apolipoproteins (apoA-I, apoB, and apoE), and extracellular matrix proteoglycans (biglycan and versican) were identified on adjacent sections with monospecific antibodies. Minimal extracellular PLTP was detected in nonatherosclerotic coronary arteries, but extracellular and cellular PLTP immunostaining was widespread in atherosclerotic lesions. PLTP was detected in foam cell SMCs and in foam cell macrophages, which suggests that cellular cholesterol accumulation might increase PLTP expression in both cell types. This was confirmed by in vitro studies demonstrating that cholesterol loading of macrophages leads to 2- to 3-fold increases in PLTP steady-state mRNA levels, protein expression, and activity. PLTP also was detected in an extracellular distribution, colocalizing with apoA-I, apoB, apoE, and the vascular proteoglycan biglycan. In gel mobility shift assays, both active and inactive recombinant PLTP markedly increased HDL binding to biglycan, which suggests that PLTP may mediate lipoprotein binding to proteoglycans independent of its phospholipid transfer activity. CONCLUSIONS: PLTP is present in human atherosclerotic lesions, and its distribution suggests roles for PLTP in both cellular cholesterol metabolism and lipoprotein retention on extracellular matrix.

Antibody Specificity↗
PubMed2002

Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma.

BACKGROUND: Recent studies have demonstrated that lesions of aortic sclerosis and stenosis share several similarities with lesions of atherosclerosis. In atherosclerosis, angiotensin-converting enzyme (ACE) is expressed by a subset of macrophages. This study was undertaken to determine whether ACE might be present in aortic sclerosis or stenosis lesions. METHODS AND RESULTS: Immunohistochemistry was performed on 26 paraffin-embedded human aortic valves. Monospecific antibodies were used to identify ACE, macrophages, angiotensin II type 1 receptor (AT-1 receptor), angiotensin II, and apolipoprotein B. Human low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were isolated from plasma of normal volunteers by sequential density-gradient ultracentrifugation. ACE was not present in normal valves but was present in all valves with aortic sclerosis or stenosis lesions. ACE was detected on a subset of lesion macrophages but was present primarily in an extracellular distribution, where it colocalized with apolipoprotein B. ACE was detected by Western blotting on plasma LDL but not on HDL isolated from normal volunteers. Angiotensin II, the enzymatic product of ACE, was colocalized with ACE in valve lesions. ACE also was colocalized with apolipoprotein B in an adjacent coronary atherosclerotic plaque. CONCLUSIONS: ACE is present in aortic sclerosis and stenosis lesions, where it may participate in lesion development, as is evidenced by the presence of its enzymatic product, angiotensin II. The observation of an association of ACE with LDL in both lesions and plasma suggests that LDL may deliver ACE to lesions and has implications for the role of ACE-containing LDL in other diseases, such as atherosclerosis.

Angiotensin II↗
PubMed2002

HMG CoA reductase inhibitor (statin) and aortic valve calcium.

There is no known pharmacological therapy for calcific aortic valvular sclerosis or stenosis. Because leaflet calcification occurs in areas of lipoprotein deposition, we hypothesised that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG COA) reductase inhibitors (statins) might slow aortic valve calcium (AVC) accumulation. We retrospectively identified 65 patients who had undergone two electron-beam computed tomography scans at a mean (SD) interval of 2.5 (1.6) years. 28 (43%) patients were receiving statins. Patients who were treated with statins had a 62-63% lower median rate of AVC accumulation (p=0.006) and 44-49% fewer statin patients had definite AVC progression (p=0.043). These findings suggest that statins may decrease AVC accumulation.

Aortic Valve↗
PubMed2002

Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis.

Proteoglycan accumulation within the arterial intima has been implicated in lipoprotein retention and in atherosclerosis progression in humans. Two commonly studied murine models of atherosclerosis, the apolipoprotein E (apoE)-deficient (apoE-/-) mouse and the low density lipoprotein receptor-deficient (LDLR-/-) mouse, develop arterial lesions similar to those of human atherosclerosis. However, specific proteoglycan classes that accumulate in lesions of these mice and their relation to the retention of specific apolipoproteins have not been previously determined. In this report, we characterized the distribution of proteoglycans (versican, biglycan, and perlecan) and apolipoproteins (apoB, apoA-I, and apoE) in proximal aortic lesions of chow-fed apoE-/- and LDLR-/- mice at 10, 52, and 73 weeks of age. We observed that similar to the apoE-/- mice, the LDLR-/- mice develop intermediate and advanced plaques within 52 weeks of age. Perlecan and biglycan (both are proteoglycans) appeared early in lesion development with distinct expression patterns as the plaques advanced. Versican, a major proteoglycan detected in human plaques, was mostly absent in both strains. ApoA-I and apoB were detected in early through advanced lesions in regions of proteoglycan accumulation in both strains. Our results indicate that proteoglycans may contribute to the retention of lipoproteins at the earliest stage of atherosclerosis in murine models of atherosclerosis.

Animals↗
PubMed2002

Aortic valve sclerosis as a marker of active atherosclerosis.

Aortic sclerosis is a calcific disease of the aortic valvular leaflets defined as focal leaflet thickening without significant obstruction to left ventricular outflow. Several clinical factors are associated with calcific aortic valve disease, including male sex, smoking, hypertension, age, hypercholesterolemia, and diabetes. Histologic and biochemical studies suggest similarities between the mechanisms involved in the development of aortic sclerosis and atherosclerosis, suggesting these two diseases may share common pathophysiologic mechanisms. In a recent prospective trial, the presence of aortic sclerosis was associated with an approximately 50% increase in cardiovascular mortality and myocardial infarction, even after correction for age, gender, known coronary artery disease, and clinical factors associated with a aortic sclerosis.

Aortic Valve↗
PubMed2002

Genetic variants of the hemostatic system and development of transplant coronary artery disease.

BACKGROUND: The occurrence of coronary artery disease (CAD) after heart transplantation may represent an accelerated inflammatory and thrombotic response to coronary vascular endothelial cell injury. Several common mutations involving hemostasis and cellular adhesion proteins have been associated with genetic susceptibility to native coronary heart disease. The clinical setting of heart transplantation provides a unique opportunity to examine the relative contribution of circulating (i.e., recipient) vs local vascular (i.e., donor) hemostatic components to the occurrence of CAD. METHODS: We performed genotyping for several common hemostatic polymorphisms among 53 cardiac transplant patients and their heart donors. Patients were observed for an average of 43 months, and the presence of transplant CAD was determined by coronary angiography. RESULTS: The development of transplant CAD did not relate to recipient hemostatic genotype, but 2 donor polymorphisms (PAI-1 4G/5G and alpha(2) integrin C807T) were important predictors of transplant CAD. The risk ratio (RR) of transplant CAD associated with donor PAI-1 4G/4G genotype was 2.6 (95% confidence interval [CI] 1.1-6.2) and was modified by recipient cytomegalovirus status, hyperlipidemia, diabetes, and recipient factor XIII Val34Leu genotype. The RR of transplant CAD associated with donor alpha(2) integrin 807 T/T genotype was 7.4 (95% CI, 2.5-22.0). CONCLUSIONS: Genetic and metabolic factors contributed by both donor and recipient may interact at the level of the coronary vessel wall in the development of transplant-associated CAD, and this finding may provide additional support for the importance of local thrombotic response to endothelial injury in the pathogenesis of this disorder.

Adolescent↗
PubMed2002

Reproducibility of electron-beam CT measures of aortic valve calcification.

RATIONALE AND OBJECTIVES: The authors performed this study to establish the interscan, interobserver, and intraobserver reproducibility of aortic valve calcification (AVC) measurements obtained with electron-beam computed tomography (CT). MATERIALS AND METHODS: The authors evaluated electron-beam CT scans from all patients who had undergone two serial examinations on the same day as part of a study of coronary artery calcification reproducibility. In patients in whom aortic valve calcium was identified at electron-beam CT, AVC scores were measured with both the Agatston and the volumetric methods, which were developed previously to quantify coronary calcium. RESULTS: Forty-four asymptomatic patients (mean age, 66 years +/- 9) with AVC at electron-beam CT were included in the analyses. AVC score reproducibility was excellent with both the Agatston and the volumetric methods (R2 = 0.99, P = .0001 for both), with median interscan variabilities of 7% and 6.2%, respectively. Interscan reproducibility was similar, whether the analysis included all scans or was restricted to those with scores greater than 10 or greater than 30. For the volumetric method, the median interobserver variability was 5% and the median intraobserver variability was 1%. CONCLUSION: The low interscan, interobserver, and intraobserver variabilities at electron-beam CT suggest that this method should be useful for the noninvasive monitoring of AVC changes over time and for assessing the efficacy of therapies aimed at slowing AVC accumulation.

Aged↗
PubMed2002

Orthodontic undergraduate education: developments in a modern curriculum.

This paper explores some modern concepts of teaching and learning, including cognitive theory, the zone of proximal development, constructivism, andragogy and learning styles and describes how they have informed the development of an undergraduate orthodontic curriculum. The changes described include student-centred learning, guided self-learning, and the incorporation of problem-based learning concepts. The details of the problem-based learning programme are described together with results of student feedback on the change in teaching and learning style.

Adult↗