Journal of cardiovascular pharmacology and therapeutics, 1996
BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-den... more BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. METHODS AND RESULTS: In this multicenter, prospective, randomized trial, 180 patients with hypercholesterolemia and hypertriglyceridemia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total, low-density lipoprotein, and very low-density lipoprotein cholesterol and triglyceride...
An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in... more An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in which the recipient is transplanted with autologous hepatocytes that are genetically corrected with recombinant retroviruses carrying the LDL receptor. We describe the treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver. She tolerated the procedures well and in situ hybridization of liver tissue four months after therapy revealed evidence for engraftment of transgene expressing cells. The patient's LDL/HDL ratio declined from 10-13 before gene therapy to 5-8 following gene therapy, improvements which have remained stable for the duration of the treatment (18 months). This represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.
Homozygous familial hypercholesterolemia is a rare, serious disorder with a substantial reduction... more Homozygous familial hypercholesterolemia is a rare, serious disorder with a substantial reduction in low-density lipoprotein (LDL) receptor function, severely elevated LDL cholesterol, cardiovascular disease, and often death in childhood. Response to conventional drug therapies is modest. Monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK9) reduce LDL cholesterol in heterozygous familial hypercholesterolemia. The effect in homozygous familial hypercholesterolemia is unknown and uncertain. We evaluated the efficacy and safety of AMG 145 in an open-label, single-arm, multicenter, dose-scheduling pilot study in patients with homozygous familial hypercholesterolemia. Eight patients with LDL receptor-negative or -defective homozygous familial hypercholesterolemia on stable drug therapy were treated with subcutaneous 420 mg AMG 145 every 4 weeks for ≥12 weeks, followed by 420 mg AMG 145 every 2 weeks for an additional 12 weeks. All patients completed both treatment pe...
Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherenc... more Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; con...
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited tre... more Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled phase 2 studies of 8 or 12 weeks duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, NCT01288443). Data were available for 102/108 patients who received alirocumab 150 mg Q2W and 74/77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% versus -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that less than 5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C). In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of LDL-C lowering.
Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of... more Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the eff ect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, d... more The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, doubleblind, placebo-controlled primary prevention trial. It is designed to test the hypothesis that in addition to a lipidlowering diet, treatment with lovastatin is more effective than placebo in reducing acute major coronary events (i.e., sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina) in a cohort with normal to mildly elevated total (180 to 264 mg/dl) and low-density lipoprotein (LDL) cholesterol (130 to 190 mg/dl) and low high-density lipoprotein (HDL) cholesterol (°45 mg/dl for men and°47 mg/dl for women). Two sites in Texas, Lackland Air Force Base in San Antonio and the University of North Texas Health Science Center in Fort Worth, will conduct the study. After at least 12 weeks of an American Heart Association Step 1 diet and 2 weeks placebo run-in, 6,605 men and women, ages 45 to 73 and 55 to 73 years, respectively, without clinical evidence of coronary heart disease, are randomized in equal numbers to either lovastatin (20 mg/day) or placebo. Study procedures maintain the blind, allowing titration of lovastatin from 20 to 40 mg/day to achieve an LDL cholesterol goal of°110 mg/dl. All par-ticipants are followed until study completion, when 320 participants have had a primary end point or a minimum of 5 years after the last participant is randomized, whichever occurs last. All end points are adjudicated by an independent committee using prespecified criteria. Unique features of this trial are (1) the inclusion of unstable angina in the primary end point to reflect the increasing trend to treat coronary heart disease aggressively before a myocardial infarction has occurred, (2) aggressive pharmacologic intervention, with titration, to attain an LDL cholesterol goal less than the current National Cholesterol Education Panel guidelines for primary prevention, and (3) a cohort that includes women, the elderly, and those with mild to moderate hyperlipidemia and low HDL cholesterol. Compared with earlier studies, results will be applicable to a broader population and may help clarify the role of aggressive LDL cholesterol reduction measures in primary prevention. Treatment of this population is likely to realize the greatest cumulative long-term benefit in the prevention of acute major coronary events. ᮊ 1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;80:287-293) F or large segments of the U.S. population at increased risk of coronary heart disease (CHD), specifically, those with total cholesterol ú240 mg/ dl, low high-density lipoprotein (HDL) cholesterol and the elderly, the effect of risk factor modification with aggressive low-density lipoprotein (LDL) cholesterol reduction remains unknown. The relation between plasma cholesterol concentration and CHD mortality rate is continuous, graded, and strong, with no evidence of a threshold effect at either limit. 1-3 Most coronary events occur in persons who do not have high total cholesterol. In the Multiple Risk Factor Intervention trial, most events occurred in participants with a total cholesterol of 182 to 264 mg/dl, 4 and in the Framingham Heart Study, 40% of partic-
Advances in next-generation sequencing technology have enabled systematic exploration of the cont... more Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.
We evaluated C-reactive protein (C-RP), a quantitative marker of the acute phase response, as a p... more We evaluated C-reactive protein (C-RP), a quantitative marker of the acute phase response, as a potential biomarker of prevalent and incident osteoarthritis of the knee (OAK). Serum C-reactive protein concentrations were characterized with ultrasensitive rate nephelometry in a population-based sample of 1025 women (318 African-American and 707 Caucasian) who are enrollees in a study of musculoskeletal conditions at the mid-life. Assignment of OAK was based on Kellgren-Lawrence (K-L) scores of 2 or more on radiographs. Prevalent OAK was based on the baseline (1996) score while the classification of incident OAK was based on a score of 2 or greater at the follow-up examination 2.5 years later amongst those with a baseline K-L scores of 0 or 1. At baseline, the prevalence of radiographic OAK was 12% in participants who were aged 27-53 years and 18% in the subgroup of women aged 40-53 years. The mean C-RP value was 2.31 mg/L, with values ranging from below detection (0.3 mg/L) to 47.4 mg/L. Higher C-RP concentrations were associated with both prevalent and incident OAK (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001, and P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001, respectively). For each K-L score increase from 0 to 3, there was a significantly higher mean C-RP value. Compared to women without incident OAK, women who developed OAK in the 2.5-year follow-up had significantly higher baseline C-RP concentrations. Women with bilateral OAK had higher C-RP concentrations than women with unilateral OAK (6.65 mg/L +/- 0.56 vs 3.63 mg/L +/- 0.42, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.007). BMI was highly correlated with C-RP (r = 0.58) and obesity was an effect modifier with respect to OAK and C-RP concentrations. When stratified according presence or absence of OAK and obesity (BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 30 kg/m2), mean C-RP values were: obesity and OAK, 6.3 +/- 0.4 mg/L; obesity but not OAK, 4.3 mg/L +/- 0.2; no obesity but OAK, 1.7 mg/L +/- 0.8; and neither obesity nor OAK, 1.3 mg/L +/- 0.2 mg/L. These stratum means were significantly different from each other, indicating a higher C-RP with OAK after accounting for obesity. C-RP, as a measure of an acute phase response and inflammation, is highly associated with OAK; however, its high correlation with obesity limits its utility as an exclusive marker for OAK.
Recent randomized clinical trials have suggested that estrogen plus progestin does not confer car... more Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI).
In view of the role of both the de novo biosynthesis and receptor-mediated uptake of cholesterol ... more In view of the role of both the de novo biosynthesis and receptor-mediated uptake of cholesterol for normal steroidogenesis, we evaluated whether extending the therapeutic dose of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to 80 mg/d would affect adrenal and gonadal steroid synthesis in men with hypercholesterolemia. To evaluate this question, we enrolled men into a multicenter randomized, placebo-controlled study lasting 12 weeks. Men with serum low-density lipoprotein cholesterol (LDL-C) more than 145 mg/dL after 6 weeks of a lipid-lowering diet were randomized to 80 mg simvastatin or placebo. Half of the subjects were asked to undergo a 6-hour infusion of corticotropin (ACTH) to evaluate cortisol synthesis, and the entire cohort received a human chorionic gonadotropin (hCG) stimulation test to assess gonadal hormone secretion using pooled serum samples taken 15 minutes apart. A total of 81 men (age, 45 ؎ 11 years; 93% Caucasian) with baseline serum LDL-C of 197 mg/dL (placebo, n ؍ 39) and 184 mg/dL (simvastatin 80 mg, n ؍ 42) completed the study. After 12 weeks, serum LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C) in the simvastatin group changed by ؊43%, ؊25%, and 8%, respectively (all P F .001). The basal cortisol level and the peak serum cortisol and area under the curve response to the 6-hour ACTH infusion were comparable between the two treatment groups at baseline and after 12 weeks. The pooled total testosterone level at baseline was 541 and 513 ng/dL in the placebo and simvastatin-treated groups, respectively, which declined to 536 ؎ 20.5 ng/dL (؊1.5%) and 474 ؎ 30.4 ng/dL (؊13.6%, P ؍ .09) after treatment (mean ؎ SD). The pooled free testosterone declined by 6.3% in the simvastatin group, versus a 4.9% increase in the placebo group (P ؍ .588), while pooled bioavailable testosterone declined 10.2% in the simvastatin group and increased 1.4% in the placebo group (P ؍ .035). There were no changes in serum gonadotropin levels or sex hormone-binding globulin (SHBG). After administration of hCG, there were no differences in the peak total pooled testosterone level before or after 12 weeks of treatment. Simvastatin 80 mg was well tolerated compared with placebo. In conclusion, basal and stimulated cortisol production was unaffected by the use of simvastatin 80 mg versus placebo. As reported with other statins and cholestyramine, there were small declines in the simvastatin-treated group for pooled total, free, and bioavailable testosterone after 12 weeks, although there was no compensatory increase in serum follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels.
Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high... more Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-infl ammatory properties. dal-PLAQUE is the fi rst multicentre study using novel non-invasive multimodality imaging to assess structural and infl ammatory indices of atherosclerosis as primary endpoints.
Journal of Vascular and Interventional Radiology, 2007
A new technique for percutaneous gastrostomy of a decompressed excluded gastric segment after Rou... more A new technique for percutaneous gastrostomy of a decompressed excluded gastric segment after Roux-en-Y gastric bypass (RYGBP) surgery is described and the results in a single institution are reviewed. Computed tomography guidance was used to place a 21-or 22-gauge needle into the lumen of the stomach and distend it to allow placement of a feeding catheter. Ten women underwent the procedure, and despite only three patients having clear access windows, gastrostomy placement was ultimately successful in all 10 patients. Percutaneous gastrostomy of the decompressed excluded gastric segment after RYGBP surgery can be challenging, but a high rate of success can be achieved.
Journal of cardiovascular pharmacology and therapeutics, 1996
BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-den... more BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. METHODS AND RESULTS: In this multicenter, prospective, randomized trial, 180 patients with hypercholesterolemia and hypertriglyceridemia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total, low-density lipoprotein, and very low-density lipoprotein cholesterol and triglyceride...
An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in... more An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in which the recipient is transplanted with autologous hepatocytes that are genetically corrected with recombinant retroviruses carrying the LDL receptor. We describe the treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver. She tolerated the procedures well and in situ hybridization of liver tissue four months after therapy revealed evidence for engraftment of transgene expressing cells. The patient's LDL/HDL ratio declined from 10-13 before gene therapy to 5-8 following gene therapy, improvements which have remained stable for the duration of the treatment (18 months). This represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.
Homozygous familial hypercholesterolemia is a rare, serious disorder with a substantial reduction... more Homozygous familial hypercholesterolemia is a rare, serious disorder with a substantial reduction in low-density lipoprotein (LDL) receptor function, severely elevated LDL cholesterol, cardiovascular disease, and often death in childhood. Response to conventional drug therapies is modest. Monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK9) reduce LDL cholesterol in heterozygous familial hypercholesterolemia. The effect in homozygous familial hypercholesterolemia is unknown and uncertain. We evaluated the efficacy and safety of AMG 145 in an open-label, single-arm, multicenter, dose-scheduling pilot study in patients with homozygous familial hypercholesterolemia. Eight patients with LDL receptor-negative or -defective homozygous familial hypercholesterolemia on stable drug therapy were treated with subcutaneous 420 mg AMG 145 every 4 weeks for ≥12 weeks, followed by 420 mg AMG 145 every 2 weeks for an additional 12 weeks. All patients completed both treatment pe...
Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherenc... more Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; con...
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited tre... more Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled phase 2 studies of 8 or 12 weeks duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, NCT01288443). Data were available for 102/108 patients who received alirocumab 150 mg Q2W and 74/77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% versus -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that less than 5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C). In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of LDL-C lowering.
Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of... more Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the eff ect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, d... more The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, doubleblind, placebo-controlled primary prevention trial. It is designed to test the hypothesis that in addition to a lipidlowering diet, treatment with lovastatin is more effective than placebo in reducing acute major coronary events (i.e., sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina) in a cohort with normal to mildly elevated total (180 to 264 mg/dl) and low-density lipoprotein (LDL) cholesterol (130 to 190 mg/dl) and low high-density lipoprotein (HDL) cholesterol (°45 mg/dl for men and°47 mg/dl for women). Two sites in Texas, Lackland Air Force Base in San Antonio and the University of North Texas Health Science Center in Fort Worth, will conduct the study. After at least 12 weeks of an American Heart Association Step 1 diet and 2 weeks placebo run-in, 6,605 men and women, ages 45 to 73 and 55 to 73 years, respectively, without clinical evidence of coronary heart disease, are randomized in equal numbers to either lovastatin (20 mg/day) or placebo. Study procedures maintain the blind, allowing titration of lovastatin from 20 to 40 mg/day to achieve an LDL cholesterol goal of°110 mg/dl. All par-ticipants are followed until study completion, when 320 participants have had a primary end point or a minimum of 5 years after the last participant is randomized, whichever occurs last. All end points are adjudicated by an independent committee using prespecified criteria. Unique features of this trial are (1) the inclusion of unstable angina in the primary end point to reflect the increasing trend to treat coronary heart disease aggressively before a myocardial infarction has occurred, (2) aggressive pharmacologic intervention, with titration, to attain an LDL cholesterol goal less than the current National Cholesterol Education Panel guidelines for primary prevention, and (3) a cohort that includes women, the elderly, and those with mild to moderate hyperlipidemia and low HDL cholesterol. Compared with earlier studies, results will be applicable to a broader population and may help clarify the role of aggressive LDL cholesterol reduction measures in primary prevention. Treatment of this population is likely to realize the greatest cumulative long-term benefit in the prevention of acute major coronary events. ᮊ 1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;80:287-293) F or large segments of the U.S. population at increased risk of coronary heart disease (CHD), specifically, those with total cholesterol ú240 mg/ dl, low high-density lipoprotein (HDL) cholesterol and the elderly, the effect of risk factor modification with aggressive low-density lipoprotein (LDL) cholesterol reduction remains unknown. The relation between plasma cholesterol concentration and CHD mortality rate is continuous, graded, and strong, with no evidence of a threshold effect at either limit. 1-3 Most coronary events occur in persons who do not have high total cholesterol. In the Multiple Risk Factor Intervention trial, most events occurred in participants with a total cholesterol of 182 to 264 mg/dl, 4 and in the Framingham Heart Study, 40% of partic-
Advances in next-generation sequencing technology have enabled systematic exploration of the cont... more Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.
We evaluated C-reactive protein (C-RP), a quantitative marker of the acute phase response, as a p... more We evaluated C-reactive protein (C-RP), a quantitative marker of the acute phase response, as a potential biomarker of prevalent and incident osteoarthritis of the knee (OAK). Serum C-reactive protein concentrations were characterized with ultrasensitive rate nephelometry in a population-based sample of 1025 women (318 African-American and 707 Caucasian) who are enrollees in a study of musculoskeletal conditions at the mid-life. Assignment of OAK was based on Kellgren-Lawrence (K-L) scores of 2 or more on radiographs. Prevalent OAK was based on the baseline (1996) score while the classification of incident OAK was based on a score of 2 or greater at the follow-up examination 2.5 years later amongst those with a baseline K-L scores of 0 or 1. At baseline, the prevalence of radiographic OAK was 12% in participants who were aged 27-53 years and 18% in the subgroup of women aged 40-53 years. The mean C-RP value was 2.31 mg/L, with values ranging from below detection (0.3 mg/L) to 47.4 mg/L. Higher C-RP concentrations were associated with both prevalent and incident OAK (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001, and P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001, respectively). For each K-L score increase from 0 to 3, there was a significantly higher mean C-RP value. Compared to women without incident OAK, women who developed OAK in the 2.5-year follow-up had significantly higher baseline C-RP concentrations. Women with bilateral OAK had higher C-RP concentrations than women with unilateral OAK (6.65 mg/L +/- 0.56 vs 3.63 mg/L +/- 0.42, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.007). BMI was highly correlated with C-RP (r = 0.58) and obesity was an effect modifier with respect to OAK and C-RP concentrations. When stratified according presence or absence of OAK and obesity (BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 30 kg/m2), mean C-RP values were: obesity and OAK, 6.3 +/- 0.4 mg/L; obesity but not OAK, 4.3 mg/L +/- 0.2; no obesity but OAK, 1.7 mg/L +/- 0.8; and neither obesity nor OAK, 1.3 mg/L +/- 0.2 mg/L. These stratum means were significantly different from each other, indicating a higher C-RP with OAK after accounting for obesity. C-RP, as a measure of an acute phase response and inflammation, is highly associated with OAK; however, its high correlation with obesity limits its utility as an exclusive marker for OAK.
Recent randomized clinical trials have suggested that estrogen plus progestin does not confer car... more Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI).
In view of the role of both the de novo biosynthesis and receptor-mediated uptake of cholesterol ... more In view of the role of both the de novo biosynthesis and receptor-mediated uptake of cholesterol for normal steroidogenesis, we evaluated whether extending the therapeutic dose of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to 80 mg/d would affect adrenal and gonadal steroid synthesis in men with hypercholesterolemia. To evaluate this question, we enrolled men into a multicenter randomized, placebo-controlled study lasting 12 weeks. Men with serum low-density lipoprotein cholesterol (LDL-C) more than 145 mg/dL after 6 weeks of a lipid-lowering diet were randomized to 80 mg simvastatin or placebo. Half of the subjects were asked to undergo a 6-hour infusion of corticotropin (ACTH) to evaluate cortisol synthesis, and the entire cohort received a human chorionic gonadotropin (hCG) stimulation test to assess gonadal hormone secretion using pooled serum samples taken 15 minutes apart. A total of 81 men (age, 45 ؎ 11 years; 93% Caucasian) with baseline serum LDL-C of 197 mg/dL (placebo, n ؍ 39) and 184 mg/dL (simvastatin 80 mg, n ؍ 42) completed the study. After 12 weeks, serum LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C) in the simvastatin group changed by ؊43%, ؊25%, and 8%, respectively (all P F .001). The basal cortisol level and the peak serum cortisol and area under the curve response to the 6-hour ACTH infusion were comparable between the two treatment groups at baseline and after 12 weeks. The pooled total testosterone level at baseline was 541 and 513 ng/dL in the placebo and simvastatin-treated groups, respectively, which declined to 536 ؎ 20.5 ng/dL (؊1.5%) and 474 ؎ 30.4 ng/dL (؊13.6%, P ؍ .09) after treatment (mean ؎ SD). The pooled free testosterone declined by 6.3% in the simvastatin group, versus a 4.9% increase in the placebo group (P ؍ .588), while pooled bioavailable testosterone declined 10.2% in the simvastatin group and increased 1.4% in the placebo group (P ؍ .035). There were no changes in serum gonadotropin levels or sex hormone-binding globulin (SHBG). After administration of hCG, there were no differences in the peak total pooled testosterone level before or after 12 weeks of treatment. Simvastatin 80 mg was well tolerated compared with placebo. In conclusion, basal and stimulated cortisol production was unaffected by the use of simvastatin 80 mg versus placebo. As reported with other statins and cholestyramine, there were small declines in the simvastatin-treated group for pooled total, free, and bioavailable testosterone after 12 weeks, although there was no compensatory increase in serum follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels.
Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high... more Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-infl ammatory properties. dal-PLAQUE is the fi rst multicentre study using novel non-invasive multimodality imaging to assess structural and infl ammatory indices of atherosclerosis as primary endpoints.
Journal of Vascular and Interventional Radiology, 2007
A new technique for percutaneous gastrostomy of a decompressed excluded gastric segment after Rou... more A new technique for percutaneous gastrostomy of a decompressed excluded gastric segment after Roux-en-Y gastric bypass (RYGBP) surgery is described and the results in a single institution are reviewed. Computed tomography guidance was used to place a 21-or 22-gauge needle into the lumen of the stomach and distend it to allow placement of a feeding catheter. Ten women underwent the procedure, and despite only three patients having clear access windows, gastrostomy placement was ultimately successful in all 10 patients. Percutaneous gastrostomy of the decompressed excluded gastric segment after RYGBP surgery can be challenging, but a high rate of success can be achieved.
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Papers by Evan Stein