Biomedical subjects

William Insull

Publications and source records attributed to William Insull.

11 recordsLinked to original sources

PubMed2006

Dyslipidemia and auditory function.

The relationship between dyslipidemia and hearing is unclear. This study was conducted to investigate whether elevated serum lipid levels impact auditory function in humans and in guinea pigs. In the human study, a cross-sectional study of 40 volunteers with dyslipidemia was conducted. Pure tone thresholds, distortion product otoacoustic emissions, and lipid profiles were analyzed. When controlled for patient age and sex, we found that elevated triglycerides were associated with reduced hearing. In the guinea pig study, a prospective study of animals fed a high-fat diet for 14 weeks was conducted. Although the high-fat diet led to a dramatic elevation in the average weight and total cholesterol in all animals (from 61 to 589 mg/dl), there were no meaningful changes in distortion product otoacoustic emission magnitudes. These results suggest that whereas chronic dyslipidemia associated with elevated triglycerides may reduce auditory function, short-term dietary changes may not.

Adult↗

PubMed2006

Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review.

Bile acid sequestrants (BAS) continue to command a position in the treatment of dyslipidemias 25 years after their introduction. Partial diversion of the enterohepatic circulation using BAS depletes the endogenous bile acid pool by approximately 40%, thus stimulating an increase in bile acid synthesis from cholesterol, which lowers low-density lipoprotein cholesterol (LDL-C) by 15 to 26%. Three BAS are currently used for treating hypercholesterolemia in the United States: the conventional sequestrants, cholestyramine and colestipol, and the specifically engineered BAS, colesevelam hydrochloride (HCl). Compared with conventional BAS, colesevelam HCl has enhanced specificity, greater affinity, and higher capacity for binding bile acids, due to its polymer structure engineered for bile acid sequestration. BAS are not absorbed by the intestine and thus have no systemic drug-drug interactions, but may interfere with the absorption of some drugs. Although BAS monotherapy effectively lowers LDL-C, combination therapy, especially with BAS and statins, is becoming increasingly common due to complementary mechanisms of action. Low-dose statin plus BAS combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and may have a better safety profile. Combinations of BAS with nonstatin lipid-lowering agents, including niacin, fibrates, and cholesterol absorption inhibitors, may be useful in those patients who require intensive lipid-lowering, but are statin intolerant. BAS treatment can significantly reduce coronary artery disease (CAD) progression and the risk of CAD-associated outcomes. It is also becoming clear that BAS and other therapies that manipulate the bile acid synthetic pathway may have clinically useful therapeutic effects on other metabolic disorders including type 2 diabetes.

Allylamine↗

PubMed2005

Feasibility of in vivo, multicontrast-weighted MR imaging of carotid atherosclerosis for multicenter studies.

PURPOSE: To test the image quality (ImQ) and interscan coverage of MRI for measuring carotid atherosclerosis across multiple centers. MATERIALS AND METHODS: Thirty-nine subjects from five clinical sites (site 1: n=11; site 2: n=16; site 3: n=2; site 4: n=3; site 5: n=7) were imaged on GE 1.5T scanners using a standardized carotid imaging protocol with five weightings (T1, proton density (PD), T2, time-of-flight (TOF), and contrast-enhanced (CE) T1). MR technologists from the five sites received comprehensive protocol training. A maximum coverage of 24 mm (12 slices) was designed for each of four scans (baseline and at four, eight, and 13 weeks). The adequacy of coverage was calculated as the percentage of arteries with at least six slices matched across all four scans. ImQ was evaluated using an established five-point scale for each image. ImQ>or= 3 was considered acceptable for image analysis. RESULTS: Across five sites, the mean ImQ was 3.4-4.2 for T1W, 3.6-4.4 for CE-T1W, 3.4-4.2 for PDW, 3.3-4.2 for T2W, and 3.4-4.0 for TOF. The mean ImQ per site was 3.5-4.2. All sites generated at least six-slice coverage (mean=8.0-9.1) for all index carotid arteries. CONCLUSION: The ImQ and coverage values were comparable among clinical sites using a standardized carotid imaging protocol. With comprehensive protocol training, carotid MRI is technically feasible for use in multicenter studies.

Adult↗

PubMed2005

Effects of raloxifene and low-dose simvastatin coadministration on plasma lipids in postmenopausal women with primary hypercholesterolemia.

Abstract Raloxifene and low-dose simvastatin can each reduce low-density lipoprotein (LDL) cholesterol without affecting high-density lipoprotein (HDL) cholesterol and triglycerides. The objective of this double-blind, 12-week study is to determine whether raloxifene and simvastatin coadministration gives added benefit beyond either monotherapy in affecting fasting lipoproteins and apolipoproteins. Ninety-five postmenopausal women with moderately elevated LDL cholesterol (mean, 146 mg/dL) were randomized to placebo, raloxifene 60 mg/d, simvastatin 10 mg/d, or raloxifene 60 mg/d coadministered with simvastatin 10 mg/d. Raloxifene, simvastatin, and coadministration therapy reduced mean LDL cholesterol by 10.5%, 23.3%, and 31.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo), and mean apolipoprotein B by 10.4%, 24.2%, and 30.0% from baseline, respectively ( P < .003 vs baseline; P < .02 vs placebo). Each active treatment decreased non-HDL cholesterol compared with placebo ( P < .01). Coadministration treatment was more effective than either monotherapy in reducing LDL cholesterol ( P < .05). Coadministration treatment reduced mean apolipoprotein B ( P < .001) and non-HDL cholesterol ( P < .001) when compared with raloxifene, but was not significantly different when compared with simvastatin. Coadministration therapy increased HDL cholesterol and apolipoprotein A1 levels compared with placebo ( P < .02). No significant effect on triglycerides, very low density lipoprotein cholesterol, and lipoprotein (a) occurred with any active treatment. Raloxifene, simvastatin, and the coadministration therapy were generally well tolerated with clinical adverse effects similar to placebo. No woman had clinically significant elevated liver function tests requiring drug discontinuation. Further data on safety and lipid-lowering effects are needed before raloxifene and statin coadministration may be considered as therapeutic interventions for treating postmenopausal women to achieve National Cholesterol Education Program-Adult Treatment Panel III treatment guidelines.

Adult↗

PubMed2005

Sample size calculation for clinical trials using magnetic resonance imaging for the quantitative assessment of carotid atherosclerosis.

PURPOSE: To provide sample size calculation for the quantitative assessment of carotid atherosclerotic plaque using non-invasive magnetic resonance imaging in multi-center clinical trials. METHODS. As part of a broader double-blind randomized trial of an experimental pharmaceutical agent, 20 asymptomatic placebo-control subjects were recruited from 5 clinical sites for a multi-center study. Subjects had 4 scans in 13 weeks on GE 1.5 T scanners, using TOF, T1-/PD-/T2- and contrast-enhanced Tl-weighted images. Measurement variability was assessed by comparing quantitative data from the index carotid artery over the four time points. The wall/outer wall (W/OW) ratio was calculated as wall volume divided by outer wall volume. The percent lipid-rich/necrotic core (%LR/NC) and calcification (%Ca) were measured as a proportion of the vessel wall. For %LR/NC and %Ca, only those subjects that exhibited LR/NC or Ca components were used in the analysis. RESULTS: Measurement error was 5.8% for wall volume, 3.2% for W/OW ratio, 11.1% for %LR/NC volume and 18.6% for %Ca volume. Power analysis based on these values shows that a study with 14 participants in each group could detect a 5% change in W/OW ratio, 10% change in wall volume, and 20% change in %LR/NC volume (power = 80%, p < .05). The calculated measurement errors presume any true biological changes were negligible over the 3 months that subjects received placebo. CONCLUSION: In vivo MRI is capable of quantifying plaque volume and plaque composition, such as %lipid-rich/necrotic core and %calcification, in the clinical setting of a multi-center trial with low inter-scan variability. This study provides the basis for sample size calculation of future MRI trials.

Aged↗

PubMed2004

Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals.

This study assessed whether the co-administration of ezetimibe and simvastatin would be more effective than simvastatin monotherapy in allowing high-risk patients to achieve a low-density lipoprotein (LDL) cholesterol goal of <100 mg/dl. Men and women with LDL cholesterol >/=130 mg/dl and meeting National Cholesterol Education Program Adult Treatment Panel III criteria for coronary heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily treatments for 23 weeks: simvastatin 20 mg (n = 253), ezetimibe 10 mg plus simvastatin 10 mg (n = 251), ezetimibe 10 mg plus simvastatin 20 mg (n = 109), and ezetimibe 10 mg plus simvastatin 40 mg (n = 97). In all groups, patients not at goal had their simvastatin doses doubled at weeks 6, 12, and/or 18, up to a maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal attainment (<100 mg/dl) after 5 weeks of treatment. Ezetimibe plus any dose of simvastatin produced greater reductions in LDL cholesterol and allowed more patients to achieve goal after 5 weeks (p <0.001) and at the end of the study (p <0.001) than simvastatin 20 mg alone. At 5 weeks, 75%, 83%, and 87% of patients receiving ezetimibe plus simvastatin 10, 20, and 40 mg had LDL cholesterol <100 mg/dl compared with 46% of patients receiving simvastatin 20 mg. In patients who started on ezetimibe plus simvastatin 10, 20 and 40 mg, 33%, 22%, and 12%, respectively, required simvastatin titration during the study compared with 68% of patients who started on simvastatin 20 mg. The corresponding median simvastatin doses used were 10, 20, 40, and 40 mg, respectively. Ezetimibe plus simvastatin was well tolerated, with an overall safety profile similar to that of simvastatin monotherapy. Thus, through the dual inhibition of cholesterol absorption and synthesis, ezetimibe plus simvastatin allowed more patients to reach LDL cholesterol <100 mg/dl at a lower simvastatin dose and with fewer dose titrations than simvastatin monotherapy.

Adult↗

PubMed2004

Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis.

BACKGROUND: Combination therapy to improve the total lipid profile may achieve greater coronary risk reductions than lowering low-density lipoprotein cholesterol (LDL-C) alone. A new extended-release niacin (niacin ER)/lovastatin tablet substantially lowers LDL-C, triglyceride, and lipoprotein(a) levels and raises high-density lipoprotein cholesterol (HDL-C) level. We evaluated these serum lipid responses to niacin ER/lovastatin at all clinically reasonable doses. METHODS: Men (n = 85) and women (n = 79) with type IIa or IIb primary hyperlipidemia after diet were randomized among 5 parallel treatment arms. Each arm had 5 sequential 4-week treatment periods: niacin ER (starting at 500 mg/d, increasing in 500-mg increments to 2500 mg/d); lovastatin (starting at 10 mg, increasing to 20 mg, then 40 mg/d); and 3 combinations arms, each with a constant lovastatin dose and escalating niacin ER doses. RESULTS: For primary comparisons, mean LDL-C level reductions from baseline were greater with niacin ER/lovastatin (1500/20 mg) than with lovastatin (20 mg) (35% vs 22%, P<.001) and with niacin ER/lovastatin (2000/40 mg) than with lovastatin (40 mg) (46% vs 24%, P<.001). Each 500-mg increase in niacin ER, on average, decreased LDL-C levels an additional 4% and increased HDL-C levels 8%. The maximum recommended dose (2000/40 mg/d) increased HDL-C levels 29% and decreased LDL-C levels 46%, triglyceride levels 38%, and lipoprotein(a) levels 14%. All lipid responses were dose dependent and generally additive. Graphs of the dose-response relationships as 3-dimensional surfaces documented the strength and consistency of these responses. CONCLUSIONS: Niacin ER/lovastatin combination therapy substantially improves 4 major lipoprotein levels associated with atherosclerotic disease. Dose-response surfaces provide a practical guide for dose selection.

Delayed-Action Preparations↗

PubMed2004

Tracking regression and progression of atherosclerosis in human carotid arteries using high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) can accurately and reproducibly measure the volume of atherosclerotic plaque in human carotid arteries. Atherosclerotic plaques may either progress or regress over time, depending on individual risk factors and treatment regimens. This study was designed to determine if regression or progression of human carotid atherosclerosis in patients receiving statin therapy over 24 months can be detected by high-resolution MRI. METHODS: In 11 subjects who had undergone unilateral carotid endarterectomy and were on statin therapy, volumes for total carotid artery, concentric wall (normal wall), eccentric wall (plaque), and lumen were quantified at 0, 16 and 24 months using a 1.5-T human imager equipped with 6-cm phased array coils. RESULTS: The interobserver mean coefficient of variation (CV) was lowest for the lumen volume (3.1%) and highest for the plaque volume (9.8%). The interscan mean CV was lowest for the total artery volume (3.2%) and highest for the plaque volume (9.9%). As much as 26% regression and 35% progression were observed in individual subject's carotid artery eccentric wall (plaque) volumes over time. Mean eccentric wall volume increased 5% by 16 months and 8% by 24 months. Mean total wall volume increased slightly at both 16 and 24 months (+1.2% and +1.8%). CONCLUSIONS: High-resolution MRI provides a noninvasive reproducible method of tracking changes in carotid atherosclerosis. This pilot study detected changes in individual subjects at both 16 and 24 months. MRI tracking of changes in atherosclerotic plaques should prove useful in assessing vascular disease risk and monitoring the efficacy of interventions designed to induce regression or retard progression.

Aged↗

PubMed2003

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Animals↗

PubMed2003

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Acute Disease↗

PubMed2002

Bilateral symmetry of human carotid artery atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis is a principal cause of stroke and myocardial infarction. The carotid arteries provide a site at which progression of atherosclerosis can be monitored reproducibly and noninvasively. This study was conducted to determine the similarity of atherosclerotic plaques in the left and right carotid arteries. This question was explored with the use of perfusion-fixed cadaveric carotid arteries and 2 noninvasive clinical imaging techniques, MRI and electron-beam CT. METHODS: Fifty pairs of carotid arteries from cadaveric donors (aged 48 to 98 years) were imaged with MRI and electron-beam CT. Thirty-eight of the pairs met the criteria for rigorous analysis. Carotid artery wall volumes were measured from the MRI images, and calcification scores were computed from the electron-beam CT images. RESULTS: Total wall volumes of the left (972.5+/-241.6 mm3) and right (1016.3+/-275.0 mm3) carotid arteries were moderately correlated (concordance correlation coefficient [r(c)]=0.71). Calcification scores were highly correlated, with r(c)=0.95 for the Agatston scores and r(c)=0.94 for the calcium volume scores. CONCLUSIONS: Total wall volume and plaque calcification in the left and right human carotid arteries are substantially similar. These results suggest that atherosclerosis of the human carotid arteries is generally a bilaterally symmetrical disease. This evidence of symmetry suggests that diagnostic information about atherosclerotic plaque in one carotid artery can be used to infer information about the composition and volume of atherosclerotic plaque in the contralateral artery.

Aged↗