Gordon A. Francis

2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations

The present article represents the 2009 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult.

2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult

Many developments have occurred since the publication of the widely-used 2009 Canadian Cardiovascular Society (CCS) Dyslipidemia guidelines. Here, we present an updated version of the guidelines, incorporating new recommendations based on recent findings and harmonizing CCS guidelines with those from other Societies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used, per present standards of the CCS. The total cardiovascular disease Framingham Risk Score (FRS), modified for a family history of premature coronary disease, is recommended for risk assessment. Low-density lipoprotein cholesterol remains the primary target of therapy. However, non-high density lipoprotein cholesterol has been added to apolipoprotein B as an alternate target. There is an increased emphasis on treatment of higher risk patients, including those with chronic kidney disease and high risk hypertension. The primary panel has recommended a judicious use of secondary testing for subjects in whom the need for statin therapy is unclear. Expanded information on health behaviours is presented and is the backbone of risk reduction in all subjects. Finally, a systematic approach to statin intolerance is advocated to maximize appropriate use of lipid-lowering therapy. This document presents the recommendations and principal conclusions of this process. Along with associated Supplementary Material that can be accessed online, this document will be part of a program of knowledge translation. The goal is to increase the appropriate use of evidence-based cardiovascular disease event risk assessment in the management of dyslipidemia as a fundamental means of reducing global risk in the Canadian population.

Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier Disease.

Tangier disease is a rare genetic disorder characterized by extremely low plasma levels of HDL and apo A-I, deposition of cholesteryl esters in tissues, and a high prevalence of cardiovascular disease. We examined the possibility that HDL apolipoprotein-mediated removal of cellular lipids may be defective in Tangier disease. With fibroblasts from normal subjects, purified apo A-I cleared cells of cholesteryl esters, depleted cellular free cholesterol pools available for esterification, and stimulated efflux of radiolabeled cholesterol, phosphatidylcholine, and sphingomyelin. With fibroblasts from two unrelated Tangier patients, however, apo A-I had little or no effect on any of these lipid transport processes. Intact HDL also was unable to clear cholesteryl esters from Tangier cells even though it promoted radiolabeled cholesterol efflux to levels 50-70% normal. Passive desorption of radiolabeled cholesterol or phospholipids into medium containing albumin or trypsinized HDL was normal for Tangier cells. Binding studies showed that the interaction of apo A-I with high-affinity binding sites on Tangier fibroblasts was abnormal. These results indicate that apo A-I has an impaired ability to remove cholesterol and phospholipid from Tangier fibroblasts, possibly because of a defective interaction of apo A-I with cell-surface binding sites. Failure of apo A-I to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles and the low plasma HDL levels in Tangier disease.

Contribution of Intimal Smooth Muscle Cells to Cholesterol Accumulation and Macrophage-Like Cells in Human Atherosclerosis

Background— Intimal smooth muscle cells (SMCs) contribute to the foam cell population in arterial plaque, and express lower levels of the cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) in comparison with medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 in comparison with intimal monocyte-derived macrophages, however, are unknown. Although the expression of macrophage markers by SMCs following lipid loading has been described, the relevance of this phenotypic switch by SMCs in human coronary atherosclerosis has not been determined. Methods and Results— Human coronary artery sections from hearts explanted at the time of transplantation were processed to clearly delineate intracellular and extracellular lipids and allow costaining for cell-specific markers. Costaining for oil red O and the SMC-specific marker SM &agr;-actin of foam cell–rich lesions revealed that 50±7% (average±standard error of the mean, n=14 subjects) of total foam cells were SMC derived. ABCA1 expression by intimal SMCs was significantly reduced between early and advanced atherosclerotic lesions, with no loss in ABCA1 expression by myeloid lineage cells. Costaining with the macrophage marker CD68 and SM &agr;-actin revealed that 40±6% (n=15) of CD68-positive cells originated as SMCs in advanced human coronary atherosclerosis. Conclusions— These findings suggest SMCs contain a much larger burden of the excess cholesterol in human coronary atherosclerosis than previously known, in part, because of their relative inability to release excess cholesterol via ABCA1 in comparison with myeloid lineage cells. Our results also indicate that many cells identified as monocyte-derived macrophages in human atherosclerosis are in fact SMC derived.

Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease

The cholesterol trafficking defect in Niemann-Pick type C (NPC) disease leads to impaired regulation of cholesterol esterification, cholesterol synthesis, and low density lipoprotein receptor activity. The ATP-binding cassette transporter A1 (ABCA1), which mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, is also regulated by cell cholesterol content. To determine whether the Niemann-Pick C1 protein alters the expression and activity of ABCA1, we determined the ability of apolipoprotein A-I (apoA-I) to deplete pools of cellular cholesterol and phospholipids in human fibroblasts derived from NPC1+/+, NPC1+/–, and NPC1–/– subjects. Efflux of low density lipoprotein-derived, non-lipoprotein, plasma membrane, and newly synthesized pools of cell cholesterol by apoA-I was diminished in NPC1–/– cells, as was efflux of phosphatidylcholine and sphingomyelin. NPC1+/– cells showed intermediate levels of lipid efflux compared with NPC1+/+ and NPC1–/– cells. Binding of apoA-I to cholesterol-loaded and non-cholesterol-loaded cells was highest for NPC1+/– cells, with NPC1+/+ and NPC1–/– cells showing similar levels of binding. ABCA1 mRNA and protein levels increased in response to cholesterol loading in NPC1+/+ and NPC1+/– cells but showed low levels at base line and in response to cholesterol loading in NPC1–/– cells. Consistent with impaired ABCA1-dependent lipid mobilization to apoA-I for HDL particle formation, we demonstrate for the first time decreased plasma HDL-cholesterol levels in 17 of 21 (81%) NPC1–/– subjects studied. These results indicate that the cholesterol trafficking defect in NPC disease results in reduced activity of ABCA1, which we suggest is responsible for the low HDL-cholesterol in the majority of NPC subjects and partially responsible for the overaccumulation of cellular lipids in this disorder.

High density lipoprotein oxidation: in vitro susceptibility and potential in vivo consequences.

Elevated levels of plasma high density lipoprotein (HDL) are strongly predictive of protection against atherosclerotic vascular disease. HDL particles likely have several beneficial actions in vivo, including the initiation of reverse cholesterol transport. The apparent importance of oxidative modification of low density lipoprotein in atherogenesis raises the question of how oxidative modification of HDL might affect its cardioprotective actions. HDL is readily oxidized using numerous models of lipoprotein oxidation. In vitro evidence suggests oxidation might impair some protective actions, but actually enhance other mechanisms induced by HDL that prevent the accumulation of cholesterol in the artery wall. This article reviews the current literature concerning the relative oxidizability of HDL, the structural changes induced in HDL by oxidation in vitro, and the potential consequences of oxidative modification on the protective actions of HDL in vivo.

Benefits of high-dose, high-frequency interferon beta-1a in relapsing–remitting multiple sclerosis are sustained to 16 months: Final comparative results of the EVIDENCE trial

The EVIDENCE trial demonstrated that interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw) (Rebif), was significantly more effective than IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw) (Avonex), in reducing relapses and magnetic resonance imaging (MRI) activity in patients with relapsing-remitting multiple sclerosis at both 24 and 48 weeks of therapy. We now present final comparative data on these patients, showing that the superior efficacy of IFN beta-1a, 44mcg sc tiw, for relapse measures and MRI activity, compared with IFN beta-1a, 30mcg im qw, was sustained for at least 16 months. The development of antibodies to IFN was associated with reduced efficacy on MRI measures and fewer IFN-related adverse events, but did not have an impact on relapse outcomes.

Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation

Smooth muscle cells (SMCs) are the main cell type in intimal thickenings and some stages of human atherosclerosis. Like monocyte-derived macrophages, SMCs accumulate excess lipids and contribute to the total intimal foam cell population. In contrast, apolipoprotein (Apo)E-deficient and LDL receptor-deficient mice develop atherosclerotic lesions that are macrophage- as opposed to SMC-rich. The lesser contribution of SMCs to lesion development in these mouse models has distracted attention away from the importance of SMC cholesterol homeostasis in the artery wall. Intimal SMCs accumulate excess amounts of cholesteryl esters when compared with medial layer SMCs, possibly explained by reduced ATP-binding cassette transporter A1 expression and ApoA-I binding to intimal-type SMCs. The aim of this review is to compare the relative contribution of monocyte-derived macrophages and SMCs to human vs. mouse atherosclerosis, and describe what is known about lipid uptake and removal mechanisms contributing to arterial macrophage and SMC foam cell formation. An increased understanding of the contribution of these cell types to lesion development will help to delineate their relative importance in atherogenesis and as potential therapeutic targets.

Vascular Calcifications in Homozygote Familial Hypercholesterolemia

Background—Patients with homozygous familial hypercholesterolemia (hmzFH) attributable to LDL receptor gene mutations have shown a remarkable increase in survival over the last 20 years. Early onset coronary heart disease (CHD) and calcific aortic valve stenosis are the major complications of this disorder. We now report extensive premature calcification of the aorta in patients with hmzFH. Methods and Results—We examined 25 hmzFH patients from Canada; mean age was 32 years (range 5 to 54), and mean baseline cholesterol before treatment was 19±5 mmol/L (737±206 mg/dL). Aortic calcification was quantified using computed tomography (CT). An elevated mean calcium score was found in patients by age 20 and correlated with age (r2=0.53, P=0.001). One quarter (24%) of patients underwent aortic valve surgery. Conclusions—We document premature severe aortic calcifications in all adult hmzFH patients studied. These presented considerable surgical management challenges. Strategies to identify and monitor aortic calcification in hmzFH by noninvasive techniques are required, as are clinical trials to determine whether additional or more intensive therapies will prevent the progression of such calcifications. Whether vascular calcifications in hmzFH subjects are related to sustained increases in LDL-C levels or to other mechanisms, such as abnormal osteoblast activity, remains to be determined.

Enhanced cholesterol efflux by tyrosyl radical-oxidized high density lipoprotein is mediated by apolipoprotein AI-AII heterodimers

Myeloperoxidase secreted by phagocytes in the artery wall may be a catalyst for lipoprotein oxidation. High density lipoprotein (HDL) oxidized by peroxidase-generated tyrosyl radical has a markedly enhanced ability to deplete cultured cells of cholesterol. We have investigated the structural modifications in tyrosylated HDL responsible for this effect. Spherical reconstituted HDL (rHDL) containing the whole apolipoprotein (apo) fraction of tyrosylated HDL reproduced the ability of intact tyrosylated HDL to enhance cholesterol efflux from cholesterol-loaded human fibroblasts when reconstituted with the whole lipid fraction of either HDL or tyrosylated HDL. Free apoAI or apoAII showed no increased capacity to induce cholesterol efflux from cholesterol-loaded fibroblasts following oxidation by tyrosyl radical, either in their lipid-free forms or in rHDL. The product of oxidation of a mixture of apoAI and apoAII (1:1 molar ratio) by tyrosyl radical, however, reproduced the enhanced ability of tyrosylated HDL to induce cholesterol efflux when reconstituted with the whole lipid fraction of HDL. HDL containing only apoAI or apoAII showed no enhanced ability to promote cholesterol efflux following oxidation by tyrosyl radical, whereas HDL containing both apoAI and apoAII did. rHDL containing apoAI-apoAIImonomer and apoAI-(apoAII)2heterodimers showed a markedly increased ability to prevent the accumulation of LDL-derived cholesterol mass by sterol-depleted fibroblasts compared with other apolipoprotein species of tyrosylated HDL. These results indicate a novel product of HDL oxidation, apoAI-apoAII heterodimers, with a markedly enhanced capacity to deplete cells of the regulatory pool of free cholesterol and total cholesterol mass. The recent observation of tyrosyl radical-oxidized LDL in vivo suggests that a similar modification of HDL would significantly enhance its ability to deplete peripheral cells of cholesterol in the first step of reverse cholesterol transport.