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Biomedical subjects

C M Ballantyne

Publications and source records attributed to C M Ballantyne.

At least 73 records · Page 4Linked to original sources
PubMed1998

Clinical trial endpoints: angiograms, events, and plaque instability.

Clinical trials provide evidence on methods for risk assessment of coronary artery disease and on interventions used to decrease risk. Plaque rupture, which leads to either progression of coronary artery disease or myocardial infarction, is the critical biologic event in the pathophysiology of atherothrombosis that leads to morbidity and mortality. Trials with endpoints of myocardial infarction and death provide direct information on the effect of intervention on morbidity and mortality, but these trials require extremely large sample sizes and long duration. To obtain clinical information more quickly and with fewer patients, investigators have conducted trials using surrogate endpoints that examine the effect of treatment on the underlying disease process through measures of atherosclerotic lesion progression and/or regression and new lesion development. Coronary angiography studies have consistently shown that lipid-modifying therapy decreases coronary artery disease progression. The correlation between rate of progression of coronary artery disease and clinical coronary events such as myocardial infarction and coronary death may be explained by the relation of both to the biologic process of plaque rupture and thrombosis.

Clinical Trials as Topic↗
PubMed1998

Stem cell factor induction is associated with mast cell accumulation after canine myocardial ischemia and reperfusion.

BACKGROUND: Myocardial infarction is associated with an intense inflammatory reaction leading to healing and scar formation. Because mast cells are a significant source of fibrogenic factors, we investigated mast cell accumulation and regulation of stem cell factor (SCF), a potent growth and tactic factor for mast cells, in the healing myocardium. METHODS AND RESULTS: Using a canine model of myocardial ischemia and reperfusion, we demonstrated a striking increase of mast cell numbers during the healing phase of a myocardial infarction. Mast cell numbers started increasing after 72 hours of reperfusion, showing maximum accumulation in areas of collagen deposition (12.0+/-2.6-fold increase; P<0.01) and proliferating cell nuclear antigen (PCNA) expression. The majority of proliferating cells were identified as alpha-smooth muscle actin-positive myofibroblasts or factor VIII-positive endothelial cells. Mast cells did not appear to proliferate. Using a nuclease protection assay, we demonstrated induction of SCF mRNA within 72 hours of reperfusion. Immunohistochemical studies demonstrated that a subset of macrophages was the source of SCF immunoreactivity in the infarcted myocardium. SCF protein was not found in endothelial cells and myofibroblasts. Intravascular tryptase-positive, FITC-avidin-positive, CD11b-negative mast cell precursors were noted in the area of healing and in the cardiac lymph after 48 to 72 hours of reperfusion. CONCLUSIONS: Mast cells increase in number in areas of collagen deposition and PCNA expression after myocardial ischemia. The data provide evidence of mast cell precursor infiltration into the areas of cellular injury. SCF is induced in a subset of macrophages infiltrating the healing myocardium. We suggest an important role for SCF in promoting chemotaxis and growth of mast cell precursors in the healing heart.

Animals↗
PubMed1998

Current thinking in lipid lowering.

In addition to elevated low-density lipoprotein (LDL) cholesterol, which has been conclusively proven to play a critical role in atherogenesis and coronary artery disease (CAD), other lipoprotein abnormalities are associated with CAD, such as reduced high-density lipoprotein (HDL) cholesterol; increased triglyceride-rich lipoproteins (very low density and intermediate-density lipoproteins); increased lipoprotein(a); small, dense LDL; and LDL with increased susceptibility to oxidation. Other, nonlipid factors such as homocysteine, fibrinogen, C-reactive protein, and soluble cell adhesion molecules may also have a role in risk stratification. The present US treatment guidelines, which focus on LDL cholesterol, stratify risk assessment and intensity of treatment by the presence of CAD; therefore, noninvasive imaging techniques such as ultrafast computed tomography and positron-emission tomography (PET) of the heart, which enable early detection of CAD, are useful in risk assessment. Because the influence of risk factors depends on their severity and combination, global risk assessment provides a necessary guide to the appropriate intensity of treatment. Agents are available that reduce LDL cholesterol and triglyceride and increase HDL cholesterol; although lipoprotein(a), LDL particle size, LDL oxidation, and homocysteine can also be altered, the clinical effects of such alterations are not known. Combination therapy that simultaneously improves multiple components of the lipid profile may provide additional benefit compared with monotherapy. To provide cost-effective treatment to the most patients, high-risk patients must be identified through systematic screening. Then each patient should be treated with the most cost-effective agent(s) that will enable achievement of the lipid levels recommended in the guidelines.

Cholesterol, HDL↗
PubMed1998

Cytokines and the microcirculation in ischemia and reperfusion.

The intense inflammatory reaction following reperfusion of the infarcted myocardium has been implicated as a factor in extension of injury. However, this inflammatory reaction is also critical to tissue repair. The cellular responses that mediate these functions are orchestrated by sequential induction and/or release of cytokines resulting in a closely regulated cytokine cascade. This paper reviews research on these cytokine cascades, their cellular origin, and factors which control the cellular response to their presence. Factors examined include leukotaxis, phenotypic transition of leukocytes, adhesion molecule induction and the role of cytokines in tissue repair and scar formation.

Animals↗
PubMed1998

Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion.

Hypertriglyceridemia may contribute to the development of atherosclerosis by increasing expression of cell adhesion molecules (CAMs). Although the cellular expression of CAMs is difficult to assess clinically, soluble forms of CAMs (sCAMs) are present in the circulation and may serve as markers for CAMs. In this study, we examined the association between sCAMs and other risk factors occurring with hypertriglyceridemia, the effect of triglyceride reduction on sCAM levels, and the role of soluble vascular cell adhesion molecule-1 (sVCAM-1) in monocyte adhesion in vitro. Compared with normal control subjects (n=20), patients with hypertriglyceridemia and low HDL (n=39) had significantly increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) (316+/-28.8 versus 225+/-16.6 ng/mL), sVCAM-1 (743+/-52.2 versus 522+/-43.6 ng/mL), and soluble E-selectin (83+/-5.9 versus 49+/-3.6 ng/mL). ANCOVA showed that the higher sCAM levels in patients occurred independently of diabetes mellitus and other risk factors. In 27 patients who received purified n-3 fatty acid (Omacor) 4 g/d for > or =7 months, triglyceride level was reduced by 47+/-4.6%, sICAM-1 level was reduced by 9+/-3.4% (P=.02), and soluble E-selectin level was reduced by 16+/-3.2% (P<.0001), with the greatest reduction in diabetic patients. These results support previous in vitro data showing that disorders in triglyceride and HDL metabolism influence CAM expression and treatment with fish oils may alter vascular cell activation. In a parallel-plate flow chamber, recombinant sVCAM-1 at the concentration seen in patients significantly inhibited adhesion of monocytes to interleukin-1-stimulated cultured endothelial cells under conditions of flow by 27.5+/-7.2%. Thus, elevated sCAMs may negatively regulate monocyte adhesion.

Adolescent↗
PubMed1997

Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study.

BACKGROUND: Recruitment of circulating leukocytes at sites of atherosclerosis is mediated through a family of adhesion molecules. The function of circulating forms of these adhesion molecules remains unknown, but their levels may serve as molecular markers of subclinical coronary heart disease (CHD). METHODS AND RESULTS: To determine the ability of circulating vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intercellular adhesion molecule-1 (ICAM-1) to serve as molecular markers of atherosclerosis and predictors of incident CHD, we studied 204 patients with incident CHD, 272 patients with carotid artery atherosclerosis (CAA), and 316 control subjects from the large, biracial Atherosclerosis Risk In Communities (ARIC) study. Levels of VCAM-1 were not significantly different among the patients with incident CHD, those with CAA, and control subjects. Higher levels of E-selectin and ICAM-1 were observed for the patients with CHD (means [ng/mL]: E-selectin, 38.4; ICAM-1, 288.7) and those with CAA (E-selectin, 41.5; ICAM-1, 283.6) compared with the control subjects (E-selectin, 32.8; ICAM-1, 244.2), but the distributions were not notably different between the patients with CHD and CAA. Results of logistic regression analyses indicated that the relationship of ICAM-1 and E-selectin with CHD and CAA was independent of other known CHD risk factors and was most pronounced in the highest quartile. The odds of CHD and CAA were 5.53 (95% CI, 2.51-12.21) and 2.64 (95% CI, 1.40-5.01), respectively, for those with levels of ICAM-1 in the highest quartile compared with those in the lowest quartile. Odds of CAA were 2.03 (95% CI, 1.14-3.62) for those with levels of E-selectin in the highest quartile compared with those in the lowest quartile. CONCLUSIONS: These data indicate that plasma levels of ICAM-1 and E-selectin may serve as molecular markers for atherosclerosis and the development of CHD.

Arteriosclerosis↗
PubMed1997

Phagocytes in ischemia injury.

We are now developing the means to evaluate components of this inflammatory response that may facilitate healing. A key event in the change in the inflammatory response is the development of a cytokine cascade that promotes phenotypic changes in the infiltrating leukocytes, which endow them with the ability to promote fibroblast proliferation and collagen deposition, the hallmarks of healing.

Animals↗
PubMed1997

Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]).

Despite the potential for reduced morbidity and mortality, aggressive intervention against mild to moderate hypercholesterolemia in patients with coronary heart disease (CHD) remains controversial and infrequently practiced. Eligible patients in the 2.5-year Lipoprotein and Coronary Atherosclerosis Study were men and women aged 35 to 75 years with angiographic CHD and mean low-density lipoprotein (LDL) cholesterol of 115 to 190 mg/dl despite diet. Patients (n = 429; 19% women) were randomized to fluvastatin 20 mg twice daily or placebo. One fourth of patients were also assigned open-label adjunctive cholestyramine up to 12 g/day because prerandomization LDL cholesterol remained > or = 160 mg/dl. The primary end point, assessed by quantitative coronary angiography, was within-patient per-lesion change in minimum lumen diameter (MLD) of qualifying lesions. Across 2.5 years, mean LDL cholesterol was reduced by 23.9% in all fluvastatin patients (+/- cholestyramine) (146 to 111 mg/dl) and by 22.5% in the fluvastatin only subgroup (137 to 106 mg/dl). Primary end point analysis (340 patients) showed significantly less lesion progression in all fluvastatin versus all placebo patients, deltaMLD -0.028 versus -0.100 mm (p <0.01), and for fluvastatin alone versus placebo alone, deltaMLD -0.024 versus -0.094 mm (p <0.02). A consistent angiographic benefit with treatment was seen whether baseline LDL cholesterol was above or below 160 or 130 mg/dl. Beneficial trends with treatment were also consistently seen in clinical event rates but were not statistically significant. Thus, lipid lowering by fluvastatin in patients with mildly to moderately elevated LDL cholesterol significantly slowed CHD progression.

Adult↗
PubMed1997

LFA-1 is sufficient in mediating neutrophil emigration in Mac-1-deficient mice.

To better define the specific function of Mac-1 (CD11b) versus LFA-1 (CD11a) and the other CD11 integrins in vivo, we have disrupted murine CD11b by targeted homologous recombination in embryonic stem cells and generated mice which are homozygous for a mutation in CD11b. A null mutation was confirmed by Southern blotting, RNase protection assay, immunohistochemistry, and flow cytometry. Neutrophils isolated from mice deficient in Mac-1 were defective in adherence to keyhole limpet hemocyanin-coated glass, iC3b-mediated phagocytosis, and homotypic aggregation. When challenged by thioglycollate intraperitoneally, Mac-1-deficient mice had similar levels of neutrophil accumulation in the peritoneal cavity at 1, 2, and 4 h. Treatment with mAb to LFA-1 blocked 78% of neutrophil accumulation in Mac-1-deficient mice and 58% in wild-type mice. Neutrophil emigration into the peritoneal cavity 16 h after the implantation of fibrinogen-coated disks was not reduced in Mac-1-deficient mice whereas neutrophil adhesion to the fibrinogen-coated disks was reduced by > 90%. Neutrophils from Mac-1-deficient mice also showed reduced degranulation. Our results demonstrate that Mac-1 plays a critical role in mediating binding of neutrophils to fibrinogen and neutrophil degranulation, but is not necessary for effective neutrophil emigration, which is more dependent upon LFA-1.

Animals↗
PubMed1997

Induction of monocyte chemoattractant protein-1 in the small veins of the ischemic and reperfused canine myocardium.

BACKGROUND: Healing after myocardial infarction is characterized by the presence of macrophages in the infarcted area. Since augmented monocyte influx has been implicated as a potential mechanism for improved healing after reperfusion, we wished to study the induction of monocyte chemoattractant protein-1 (MCP-1) during reperfusion. METHODS AND RESULTS: The cDNA for MCP-1 was cloned from a canine jugular vein endothelial cell (CJVEC) library and exhibited 78% identity with the deduced amino acid sequence of human MCP-1. Samples of myocardium were taken from control and ischemic segments after 1 hour of ischemia and various times of reperfusion; total RNA was isolated from myocardial samples and probed with a cDNA probe for canine MCP-1. Induction of MCP-1 mRNA occurred only in previously ischemic segments within the first hour of reperfusion, peaked at 3 hours, and persisted throughout the first 2 days of reperfusion. In the absence of reperfusion, no significant MCP-1 induction was seen. Both ischemic (but not preischemic) cardiac lymph and human recombinant TNF-alpha induced MCP-1 in CJVECs. MCP-1 was identified by immunostaining on infiltrating cells and venular (but not arterial) endothelium by 3 hours. In contrast, in situ hybridization showed MCP-1 mRNA to be confined to the endothelium of small veins (venules) 10 to 70 microns in diameter. CONCLUSIONS: MCP-1 mRNA is induced in the endothelium of a specific class of small veins immediately after reperfusion. MCP-1 induction is confined to the previously ischemic area that has been reperfused. We suggest a significant role for MCP-1 in monocyte trafficking in the reperfused myocardium.

Amino Acid Sequence↗
PubMed1997

Pathophysiology and treatment of lipid perturbation after cardiac transplantation.

In this review we examine the complex interactions between lipoprotein metabolism, immunosuppressive drug therapy, and inflammation and the potential benefits of lipid-lowering drug therapy after heart transplantation. The newer formulations of cyclosporine, Neoral (Novartis Pharmaceuticals; Basle, Switzerland), and other newer agents such as tacrolimus may have advantages in regard to lipid metabolism as compared with traditional triple-drug immunosuppression. Lipoprotein levels may influence both the toxicity and efficacy of cyclosporine. Dyslipidemia may adversely influence inflammation and rejection in the allograft. Two recent clinical trials have shown that lipid-lowering therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor alone or in combination with low-density lipoprotein apheresis may confer significant benefits toward preventing transplant coronary artery disease.

Acyl Coenzyme A↗
PubMed1997

Effects of lipid lowering therapy on progression of coronary and carotid artery disease.

Recent data have extended the benefit of lipid lowering therapy to patients with only mildly to moderately elevated LDL-cholesterol, which is typical of patients with coronary artery disease. Meta-analysis of clinical trials of statin therapy with similar sample sizes indicated that the LDL-cholesterol level on treatment was as good a predictor of angiographic benefit as was the percentage reduction in LDL-cholesterol. We review evidence that management of triglyceride-rich lipoproteins, HDL, fibrinogen, lipoprotein particle size, LDL-oxidation, and lipoprotein (a) may also favorably influence atherosclerotic progression. Angiographic and arterial ultrasound trials of lipid lowering therapy have demonstrated benefits on disease progression that are consistent with benefits on myocardial infarction, stroke, and death reported in larger, lengthier trials.

Arteriosclerosis↗
PubMed1996

Functions of domain 1 and 4 of vascular cell adhesion molecule-1 in alpha4 integrin-dependent adhesion under static and flow conditions are differentially regulated.

To assess the potential contributions of endothelial vascular cell adhesion molecule-1 (VCAM-1) to leukocyte adhesion under conditions of flow, we evaluated the effects of cytokine stimulation of HUVEC on primary capture, rolling, and stable adhesion of mono- and lymphoblastoid cells in a parallel-plate flow chamber. Stimulation of HUVEC with IL-1beta or IL-4 for 24 h induced surface expression of VCAM-1, consistent with published results. Using blocking mAbs to inhibit specific adhesion molecules, we found that a significant level of primary capture at wall shear stresses between 0.5 and 2.0 dynes/cm2 could be attributed to alpha4 integrin and VCAM-1. This primary adhesion under flow was most often characterized by abrupt stationary adhesion with little evidence of rolling. Studies with IL-1beta-stimulated HUVEC revealed that domain 1 of VCAM-1 was solely responsible for alpha4 integrin-dependent primary capture under flow, but both domains 1 and 4 were utilized in alpha4 integrin-dependent adhesion under static conditions. In contrast to results obtained with these cytokines alone, stimulation of HUVEC with a combination of IL-1beta and IL-4 markedly reduced alpha4/VCAM-1-dependent adhesion under flow, even though the surface levels of VCAM-1 were greater than with either cytokine alone, and alpha4/VCAM-1-dependent adhesion under static conditions was intact. These results demonstrate that distinct functional differences exist between the interactions of VCAM-1 and alpha4 integrin under static and flow conditions, and they reveal the potential for endothelial modulation of adhesion under flow without altering VCAM-1-dependent adhesion under static conditions.

Animals↗
PubMed1996

Treatment of hyperlipidemia after heart transplantation and rationale for the Heart Transplant Lipid Registry.

Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation.

Anticholesteremic Agents↗
PubMed1996

Levels of soluble cell adhesion molecules in patients with dyslipidemia.

BACKGROUND: Increased expression of cell adhesion molecules (CAMs) on the vascular endothelium has been postulated to play an important role in atherogenesis. Both in vitro and in vivo studies have suggested that dyslipidemia may increase expression of CAMs. METHODS AND RESULTS: To determine whether dyslipidemia is associated with increased expression of CAMs, we examined the levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin (sE-selectin) in individuals with either hypercholesterolemia or hypertriglyceridemia and in control subjects matched for age and sex. Patients with hypertriglyceridemia had significantly higher levels of sVCAM-1 (739 +/- 69 ng/mL) compared with patients with hypercholesterolemia (552 +/- 63 ng/mL) and control subjects (480 +/- 56 ng/mL). Levels of sICAM-1 were significantly increased in both the hypercholesterolemic and hypertriglyceridemic groups (298 +/- 29 and 342 +/- 31 ng/mL, respectively) compared with the control group (198 +/- 14 ng/mL). Levels of sE-selectin were significantly increased in hypercholesterolemic patients (74 +/- 9 ng/mL) compared with control subjects (48 +/- 5 ng/mL). Ten hypercholesterolemic patients were treated aggressively with atorvastatin alone or a combination of colestipol and either atorvastatin or simvastatin for a mean of 42 weeks and had an average LDL cholesterol reduction of 51%. Comparison of soluble CAMs before and after treatment showed a significant reduction only in sE-selectin (77 +/- 11 versus 56 +/- 6 ng/mL, P < or = .03) but not for sVCAM-1 or sICAM-1. CONCLUSIONS: Although severe hyperlipidemia is associated with increased levels of soluble CAMs, aggressive lipid-lowering treatment had only limited effects on the levels. Increased levels of soluble CAMs in patients with hyperlipidemia may be a marker for atherosclerosis.

Anticholesteremic Agents↗
PubMed1996

The Lipoprotein and Coronary Atherosclerosis Study (LCAS): design, methods, and baseline data of a trial of fluvastatin in patients without severe hypercholesterolemia.

Few direct clinical data are available regarding whether cholesterol-lowering therapy should be extended to patients with coronary heart disease (CHD) and normal or only slightly elevated plasma cholesterol concentrations. The one published angiographic trial designed to examine this question found no benefit. Additional prospective data will be provided by the Lipoprotein and Coronary Atherosclerosis Study (LCAS), a randomized, double-blind, placebo-controlled trial of fluvastatin therapy (20 mg twice daily) monitored by both quantitative coronary angiography (QCA) and, in a subset of patients, positron-emission tomography (PET). Eligible subjects in LCAS were men and women 35-75 years of age with low-density lipoprotein (LDL) cholesterol of 115-190 mg/dL on stable dietary therapy and with angiographic evidence by caliper measurement of at least one coronary atherosclerotic lesion causing 30-75% diameter stenosis. Among the 429 patients randomized (mean age 58.8, 81% male), mean baseline LDL cholesterol was only 145.6 mg/dL. Any patient with mean prerandomization LDL cholesterol of 160 mg/dL or higher also received open-label adjunctive cholestyramine. The primary endpoint is within-patient per-lesion change in minimum lumen diameter (MLD) as measured by QCA at baseline and 2.5-year follow-up. All evaluable lesions had MLD at least 0.8mm less than the reference lumen diameter at either baseline or follow-up and MLD at least 25% of the reference lumen diameter at baseline. Data obtained on myocardial perfusion changes (99 patients underwent initial PET), special lipid particles, and coagulation factors may help define which patients with CHD and relatively low LDL cholesterol will benefit from lipid-lowering treatment.

Adult↗