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Biomedical subjects

A M Gotto

Publications and source records attributed to A M Gotto.

At least 37 records · Page 2Linked to original sources
PubMed2000

Insights on treating an over-the-counter-type subgroup: data from the Air Force/Texas Coronary Atherosclerosis Prevention Study Population.

The expansion of therapeutic options for management of dyslipidemia is a potentially valuable avenue for the optimal treatment of most patients at low-to-moderate risk for coronary artery disease (CAD). In primary prevention, this population is closely approximated by that of the landmark Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). In AFCAPS/TexCAPS, 6,605 men and women without evidence of CAD and with average total cholesterol (180-264 mg/dL) and low-density lipoprotein (LDL)-cholesterol (130-190 mg/dL) concentrations and low high-density lipoprotein (HDL)-cholesterol levels (< or =45 mg/dL for men, < or =47 mg/dL for women) were treated with either lovastatin or placebo for a mean of 5.2 years. With few exceptions, the characteristics of the AFCAPS/TexCAPS cohort were similar to the profile of the majority of people in the United States and that of a potential over-the-counter (OTC)-type subgroup. The dosage of lovastatin used was 20-40 mg/day, titrated to achieve an LDL-cholesterol target of < or =110 mg/dL. Treatment reduced the combined incidence of fatal and nonfatal myocardial infarction, unstable angina, and sudden cardiac death by 37% (p<0.001). The risk for fatal and nonfatal heart attack was reduced by 40% (p<0.002), and the need for coronary revascularization procedures was reduced by 33% (p = 0.01). Post hoc analysis of data from a subgroup of the AFCAPS/TexCAPS cohort resembling those in the general population who may benefit from OTC statins indicates similar benefits. The results have important implications for the identification and treatment of persons at risk for coronary disease.

Aged↗
PubMed2000

Case 3: Insulin-dependent diabetes mellitus.

Dyslipidemia secondary to insulin-dependent diabetes mellitus is common among patients whose plasma glucose levels are poorly controlled. Because of the high mortality associated with diabetes, prompt intervention to correct the dyslipidemia is warranted.

Blood Glucose↗
PubMed2000

Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

BACKGROUND: The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. METHODS AND RESULTS: With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. CONCLUSIONS: Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.

Acute Disease↗
PubMed2000

Case 2: a patient with low levels of high-density lipoprotein cholesterol.

Approximately 11% of all American men >20 years of age have low levels of high-density lipoprotein cholesterol (<35 mg/dl) in isolation, with an even higher prevalence in high-risk populations. One feature of the 1993 National Cholesterol Education Program guidelines-and the focus of this month's CME-accredited case study-is an increased emphasis on high-density lipoprotein cholesterol levels as an important aspect of risk stratification for coronary heart disease.

Cholesterol, HDL↗
PubMed2000

Hydrolysis of phospholipids by purified milk lipoprotein lipase. Effect of apoprotein CII, CIII, A and E, and synthetic fragments.

Different pyrene-labeled phospholipid monolayer vesicles were used as substrates for the bovine milk lipoprotein lipase activity. The effects of synthetic fragments of apoprotein C II were measured on the hydrolysis of 1-myristoyl-2[9(1pyrenyl)-nonanoyl] phosphatidylcholine in vesicles: The activating capacity of fragments 30-78 and 43-78, 50-78 and 55-78, compared to entire apo CII, were similar to that obtained with hydrolysable triglycerides. Our study shows that the longer the carboxy terminal fragment is, the higher is the activation. The phospholipid hydrolysis activity represents in the presence of apo C II, 36% of the triglycerides hydrolysis activity. Phospholipid hydrolysis is less dependent on activator than triglycerides hydrolysis (100% and 300% of increase with apo CII for phosphatidyl-choline and triglycerides respectively). The ratio hydrolysis without apo C II/hydrolysis with apo CII was different when other phospholipids than myrystoyl-phospatidylcholine were assayed: phosphatidyl-serine, ethanolamine, -choline, -glycerol, or diglycerides and butanoylglycerols. Fragment CIII(1) (1-40) which did not bind to lipids, had no inhibitory effect. The entire sugar moiety and the first 40 amino acids are not required for the total inhibition of LPL. Inhibition was also obtained with Apo A I, A II,C I and fragments of apo E.

Animals↗
PubMed2000

Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-gamma.

CD36, the macrophage type B scavenger receptor, binds and internalizes oxidized low density lipoprotein, a key event in the development of macrophage foam cells within atherosclerotic lesions. Expression of CD36 in monocyte/macrophages is dependent on differentiation status and exposure to soluble mediators. In this study, we investigated the effect of transforming growth factor-beta1 (TGF-beta1) and TGF-beta2 on the expression of CD36 in macrophages. Treatment of phorbol ester-differentiated THP-1 macrophages with TGF-beta1 or TGF-beta2 significantly decreased expression of CD36 mRNA and surface protein. TGF-beta1/TGF-beta2 also inhibited CD36 mRNA expression induced by oxidized low density lipoprotein and 15-deoxyDelta(12,14) prostaglandin J(2), a peroxisome proliferator-activated receptor (PPAR)-gamma ligand, suggesting that the TGF-beta1/TGF-beta2 down-regulated CD36 expression by inactivating PPAR-gamma-mediated signaling. TGF-beta1/TGF-beta2 increased phosphorylation of both mitogen-activated protein (MAP) kinase and PPAR-gamma, whereas MAP kinase inhibitors reversed suppression of CD36 and inhibited PPAR-gamma phosphorylation induced by TGF-beta1/TGF-beta2. Finally, MAP kinase inhibitors alone increased expression of CD36 mRNA and surface protein but had no effect on PPAR-gamma protein levels. Our data demonstrate for the first time that TGF-beta1 and TGF-beta2 decrease expression of CD36 by a mechanism involving phosphorylation of MAP kinase, subsequent MAP kinase phosphorylation of PPAR-gamma, and a decrease in CD36 gene transcription by phosphorylated PPAR-gamma.

CD36 Antigens↗
PubMed2000

A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary atherosclerosis and its response to therapy.

Inflammation plays a key role in susceptibility to coronary atherosclerosis and response to therapy. A diverse array of factors modulates inflammation, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and CD14 receptors on the surface of macrophages. Genes encoding for inflammatory markers have variants that regulate their expression and are potential risk factors for atherosclerosis. We prospectively analyzed the possible association of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C variants, located in the promoter regions, with the severity, progression, and response to therapy of coronary atherosclerosis in a well-characterized cohort. We studied 375 subjects enrolled in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping. Fasting plasma lipids and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. Distributions of genotypes were--for CD14: 100 CC, 184 CT, and 86 TT; IL-6: 152 GG, 153 GC, and 62 CC; and TNF-alpha: 244 GG, 110 GA, and 17 AA. The CD14 CC genotype was associated with incidence of new coronary occlusion (P=0.026); TNF-alpha AA genotype with history of myocardial infarction (MI, P=0.04), and A allele with total occlusions at baseline (P=0.027), and systolic blood pressure (P=0.046); and IL-6-174 CC genotype with baseline minimum lumen diameter (P=0.043) and reduction in lipoprotein(a) with fluvastatin (P=0.03). Otherwise, no association between the genotypes and the biochemical, angiographic, and clinical phenotypes was detected, and neither were genotype-treatment interactions. Functional variants of CD14 -260C/T, TNF-alpha -308G/A, and IL-6 -174G/C, implicated in the susceptibility to infection, are unlikely to confer major risk for susceptibility to coronary atherosclerosis and its progression or response to therapy in the LCAS population.

Adult↗
PubMed2000

The evolving role of statins in the management of atherosclerosis.

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.

Cholesterol, LDL↗
PubMed2000

Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.

OBJECTIVES: Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND: Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS: Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS: Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS: Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.

Adult↗
PubMed2000

Application of the National Cholesterol Education Program and joint European treatment criteria and clinical benefit in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

AIMS: The Air Force/Texas Coronary Atherosclerosis Prevention Study reported that diet with lovastatin, 20-40 mg daily, reduced the risk for a first coronary event by 37%. Because only 17% of this cohort would have qualified for drug therapy according to current U.S. guidelines, we assessed clinical benefit by risk categories. METHODS AND RESULTS: The main outcome measures were event rates of first acute major coronary events stratified by National Cholesterol Education Program and European criteria and target goal. Both those who would and would not be eligible for drug therapy, according to National Cholesterol Education Program guidelines, benefited from intervention. As expected, drug-eligible participants (event rate: lovastatin 1%/year, placebo 1.87%/year [relative risk 0.53, 95% confidence interval: 0.33, 0.84]) were at greater absolute risk for acute major coronary events than non-eligible participants (lovastatin 0.62%/year, placebo 0.93%/year [relative risk 0.67, 95% confidence interval: 0.51, 0.88]). Similar results were found using European guidelines for coronary risk management. Treatment to a target goal suggested a non-significant trend to greater benefit. CONCLUSIONS: The consistent relative benefit across risk categories suggests that it may be possible to improve identification of at-risk persons who would benefit from primary prevention, and to recommend appropriate goals of such treatment.

Aged↗
PubMed2000

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): baseline characteristics and comparison with USA population.

BACKGROUND: Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that treatment with lovastatin, in addition to modifications of diet and lifestyle, reduced the rate of first acute major coronary events compared with placebo in a cohort that included participants with average to mildly elevated total levels of cholesterol, and below average levels of high-density lipoprotein cholesterol, women, and elderly subjects. OBJECTIVE: To describe the baseline characteristics of the study's cohort. DESIGN: This was a double-blind, placebo-controlled, primary-prevention trial in which Americans with average to mildly elevated total levels of cholesterol [4.65-6.83 mmol/l (180-264 mg/dl)] and no clinical evidence of atherosclerotic cardiovascular disease were randomly allocated either 20-40 mg/day lovastatin or placebo in addition to a low-saturated fat, low-cholesterol diet. Baseline characteristics of the study cohort are described, and the characteristics of a USA reference population based upon NHANES III data are provided for comparison. RESULTS: The study includes 5608 men (85%) and 997 women (15%) with mean total cholesterol level 5.71 +/- 0.54 mmol/l (221 +/- 21 mg/dl), low-density lipoprotein cholesterol level 3.88 +/- 0.44 mmol/l (150 +/- 17 mg/dl), high-density lipoprotein cholesterol 0.96 +/- 0.15 mmol/l (37 +/- 6 mg/dl), and median triglyceride level 1.78 +/- 0.86 mmol/l (158 +/- 76 mg/dl). The mean age is 58 years (ranges 45-73 years for men and 55- 73 years for women). The participants are 89% white, 7% Hispanic, and 3% black. CONCLUSION: Results from AFCAPS/TexCAPS will be applicable to large segments of populations; in the USA alone, eight million share the demographic and baseline-lipid-level characteristics of the study cohort.

Aged↗
PubMed2000

Plasma lipids and other cardiovascular risk factors in Costa Rican adolescents.

This study assessed plasma lipids and other cardiovascular risk factors in adolescents in a developing Latin American country and compared those risk factors to those of adolescents in the United States of America, where the risk of heart disease is high. In a cross-sectional study, data were collected from September 1998 to April 1999 on 161 Costa Rican adolescents between the ages of 12 and 20. A general questionnaire was used to collect demographic, smoking, socioeconomic, and women's health data. Anthropometric measurements, blood pressure, and a fasting blood sample were taken. The Costa Rican males had lower levels of total cholesterol than did the Costa Rican females (mean +/- standard error of the mean (SEM), 149 +/- 6.5 mg/dL vs. 158 +/- 6.3 mg/dL). This was mainly due to lower high-density lipoprotein (HDL) cholesterol in males than in females (mean +/- SEM, 38 +/- 2.0 mg/dL vs. 44 +/- 2.4 mg/dL). As compared to the United States, adolescents in this study had lower levels of total cholesterol, largely due to lower HDL cholesterol. Both genders of Costa Ricans had levels of low-density lipoprotein (LDL) cholesterol that were similar to those of counterpart groups in the United States. Costa Rican male and female adolescents had higher LDL/HDL ratios than did their United States counterparts. Therefore, as compared to the United States, Costa Rican adolescents have an adverse lipid profile as demonstrated by a higher LDL/HDL ratio. Overweight prevalence in Costa Rica was 13%, approaching the 15% overall level of the United States.

Adolescent↗
PubMed2000

Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma.

CD36, a class B scavenger receptor, is a macrophage receptor for oxidized low density lipoprotein (OxLDL) and may play a critical role in atherosclerotic foam cell formation. We have previously demonstrated that OxLDL, macrophage-colony stimulating factor (M-CSF), and interleukin-4 (IL-4) enhanced expression of CD36. The effect of OxLDL on CD36 is due, in part, to its ability to activate the transcription factor, PPAR-gamma (peroxisome proliferator activated receptor-gamma). Other PPAR-gamma ligands (15-deoxyDelta(12,14) prostaglandin J(2) (15d-PGJ(2)) and the thiazolidinedione class of antidiabetic drugs) also increase CD36 expression. We have now evaluated signaling pathways involved in the induction of CD36. Treatment of RAW264.7 cells (a murine macrophage cell line) with protein kinase C (PKC) activators (diacylglycerol and ingenol) up-regulated CD36 mRNA expression. Specific inhibitors of PKC reduced CD36 expression in a time-dependent manner, while protein kinase A (PKA) and cyclic AMP agonists had no effect on CD36 mRNA expression. PKC inhibitors reduced basal expression of CD36 and blocked induction of CD36 mRNA by 15d-PGJ(2), OxLDL and IL-4. In addition, PKC inhibitors decreased both PPAR-gamma mRNA and protein expression and blocked induction of CD36 protein surface expression by OxLDL and 15d-PGJ(2) in human monocytes, as determined by FACS. 15d-PGJ(2) had no effect on translocation of PKC-alpha from the cytosol to the plasma membrane. These results demonstrate that two divergent physiological or pathophysiological agonists utilize a common pathway to up-regulate of CD36 gene expression. This pathway involves initial activation of PKC with subsequent PPAR-gamma activation. Defining these signaling pathways is critical for understanding and modulating expression of this scavenger receptor pathway.

Animals↗
PubMed1999

Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside.

In the more than 50 years since the founding of the National Heart, Lung, and Blood Institute and the American Heart Association, medical science has moved from an era in which hypercholesterolemia, as it is now defined, was not believed to be abnormal to one in which controlling hypercholesterolemia is known to reduce not only coronary artery disease morbidity and mortality but also total mortality. While the efforts and successes of many researchers involved in this evolution are impressive, atherosclerosis is still a major cause of death and disability in many developed nations, mostly in the form of myocardial infarction and stroke, and is an increasing cause of morbidity and mortality in developing nations. Many questions about the detailed pathogenesis of the disease remain. Elucidating the roles of high-density lipoprotein, other lipoproteins, and homocysteine, as well as the roles of cytokines and growth factors, will permit better understanding and treatment of atherosclerosis. With continuing support for research and encouragement of physicians and patients to follow recommended preventive regimens, further progress can be made against this major cause of death.

Angiography↗
PubMed1999

Lipid management in patients at moderate risk for coronary heart disease: insights from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

The results of AFCAPS/TexCAPS provide strong evidence for the benefits of primary prevention through lipid-regulating treatment across the spectrum of clinical coronary events that are often the first manifestations of atherosclerotic disease. These results reinforce current NCEP guidelines and demonstrate the need for the inclusion of HDL-C in clinical evaluations. The clear benefit observed in AFCAPS/TexCAPS reinforces the need to implement treatment in all individuals with average LDL-C and low HDL-C who may be at risk for CHD. According to estimates based on phase-2 NHANES III data (1991-1994), only 1.4 million (6.6%) of 21.1 million American adults eligible for cholesterol-lowering drug therapy by NCEP guidelines were receiving such therapy, including 14% of those eligible in secondary prevention and 4% of those eligible in primary prevention. Of diet- or drug-eligible adults, 65% received no therapy of any kind. Undertreatment of dyslipidemia continues to be a problem today. These statistics suggest that physicians must improve their efforts to reverse the toll of atherosclerotic disease through risk factor management.

Age Factors↗
PubMed1999

Three-dimensional structure of low density lipoproteins by electron cryomicroscopy.

Human low density lipoproteins (LDL) are the major cholesterol carriers in the blood. Elevated concentration of LDL is a major risk factor for atherosclerotic disease. Purified LDL particles appear heterogeneous in images obtained with a 400-kV electron cryomicroscope. Using multivariate statistical and cluster analyses, an ensemble of randomly oriented particle images has been subdivided into homogeneous subpopulations, and the largest subset was used for three-dimensional reconstruction. In contrast to the general belief that below the lipid phase-transition temperature (30 degrees C) LDL are quasi-spherical microemulsion particles with a radially layered core-shell organization, our three-dimensional map shows that LDL have a well-defined and stable organization. Particles consist of a higher-density outer shell and lower-density inner lamellae-like layers that divide the core into compartments. The outer shell consists of apolipoprotein B-100, phospholipids, and some free cholesterol.

Cryoelectron Microscopy↗