A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.

Purpose: Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown.

Methods: We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80).

Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E.

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE.

US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry.

Background: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear.

Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry.

Background: Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap.

Methods And Results: We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics.

Updated cholesterol guidelines and intensity of statin therapy.

Background: In November 2013, the American College of Cardiology and the American Heart Association released new cholesterol guidelines. Implications of these new guidelines for statin prescription remain uncertain, particularly in individuals already on statin therapy.

Objective: Our objective was to examine the impact of the guidelines on the intensity of statin therapy at a large academic medical center.

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects.

Background: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.

Methods: We performed a trial of the effects of anacetrapib on ApoB kinetics.

A pilot trial to examine the effect of high-dose niacin on arterial wall inflammation using fluorodeoxyglucose positron emission tomography.

Rationale And Objectives: Although studies have reported direct inhibition of inflammatory pathways with niacin, the effect of niacin on arterial wall inflammation remains unknown. We examined the effect of niacin on arterial (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT).

Materials And Methods: Nine statin-treated patients with coronary disease were randomized to niacin 6000 mg/day or placebo.

Statins and cognitive function: an updated review.

Ischemic heart disease remains the leading cause of death in the USA. Statins have substantially contributed to the decline in mortality due to heart disease. Historically, statins are hypothesized to be neuroprotective and beneficial in dementia, but recent reports have suggested an association with transient cognitive decline.

Lomitapide for the management of homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism resulting in extremely elevated serum levels of LDL-C and premature atherosclerotic cardiovascular disease. Treatment typically involves multiple pharmacologic agents, as well as mechanical filtration using weekly or biweekly LDL apheresis. Despite combination lipid-lowering therapy, LDL-C levels and cardiovascular morbidity and mortality remain unacceptably high in HoFH patients.

Future of cholesteryl ester transfer protein inhibitors.

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport.

Statins and cognitive function: a systematic review.

Background: Despite the U.S. Food and Drug Administration (FDA) warning regarding cognitive impairment, the relationship between statins and cognition remains unknown.

Discordance between non-HDL-cholesterol and LDL-particle measurements: results from the Multi-Ethnic Study of Atherosclerosis.

Background: Cardiovascular risk assessment incorporates measurement of atherogenic lipids such as non-HDL cholesterol (non-HDL-C). It remains uncertain under which circumstances atherogenic lipoprotein enumeration such as LDL particle number (LDL-P) differs from simultaneously acquired non-HDL-C.

Methods: Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) were deemed LDL-P > non-HDL-C discordant if they exhibited higher LDL-P than expected for simultaneously measured non-HDL-C, given the observed distribution of both in MESA.

Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations.

Background: Current cardiovascular risk assessment guidelines incorporate judicious use of C-reactive protein (CRP), carotid intima-media thickness (CIMT), and coronary artery calcium (CAC) in selected populations and describe threshold levels for higher and lower cardiovascular risk for each of the three risk refinement tests. However, the effect of these suggested thresholds of relative risk on absolute global risk remains uncertain.

Methods: Systematic permutation of risk factors provided 10-year risk estimates using the Framingham risk score, equations derived from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, and the Reynolds risk score.

Pharmacologic interactions of multidrug therapy for dyslipidemia.

Despite the best available medical therapy inclusive of statins, substantial residual risk remains for atherothrombotic cardiovascular disease. Non-statin lipid-lowering therapy may help address this critical unmet need through reduction of the levels of low-density lipoprotein and other atherogenic lipoproteins. In the past few years, several landmark trials have provided important information regarding the efficacy and safety of non-statin therapy for dyslipidemia and cardiovascular risk reduction.

Approach to the patient with extremely low HDL-cholesterol.

Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear.

Targeting high density lipoproteins in the prevention of cardiovascular disease?

Recent studies involving HDL-raising therapeutics have greatly changed our understanding of this field. Despite effectively raising HDL-C levels, niacin remains of uncertain clinical benefit. Synthetic niacin receptor agonists are unlikely to raise HDL-C or have other beneficial effects on plasma lipids.

Intraindividual variability of C-reactive protein: the Multi-Ethnic Study of Atherosclerosis.

Background: The intraindividual variability of C-reactive protein (CRP) remains uncertain. Although guidelines suggest stability of serial CRP values comparable to that of cholesterol measures, several studies indicate greater fluctuations of CRP. We sought to compare the intraindividual variability of CRP with that of cholesterol measures using the multi-ethnic study of atherosclerosis (MESA).

The evolution and refinement of traditional risk factors for cardiovascular disease.

Traditional risk factors for cardiovascular disease such as systemic hypertension and hypercholesterolemia, all described more than half a century ago, are relatively few in number. Efforts to expand the epidemiologic canon have met with limited success because of the high hurdle of causality. Fortunately, another solution to current deficiencies in risk assessment-in particular, the underestimation of risk both before and after initiation of pharmacotherapy-may exist.