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1.  Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism 
Unregulated cellular uptake of apolipoprotein B-containing lipoproteins in the arterial intima leads to the formation of foam cells in atherosclerosis. Lysosomal acid lipase (LAL) plays a crucial role in both lipoprotein lipid catabolism and excess lipid accumulation as it is the primary enzyme that hydrolyzes cholesteryl esters derived from both low density lipoprotein (LDL) and modified forms of LDL. Evidence suggests that as atherosclerosis progresses, accumulation of excess free cholesterol in lysosomes leads to impairment of LAL activity, resulting in accumulation of cholesteryl esters in the lysosome as well as the cytosol in foam cells. Impaired metabolism and release of cholesterol from lysosomes can lead to downstream defects in ATP-binding cassette transporter A1 regulation, needed to offload excess cholesterol from plaque foam cells. This review focuses on the role LAL plays in normal cholesterol metabolism and how the associated changes in its enzymatic activity may ultimately contribute to atherosclerosis progression.
PMCID: PMC4313778
lysosomal acid lipase; atherosclerosis; foam cells; oxidized LDL; lysosomal storage disorders; ABCA1; smooth muscle cells; macrophages
2.  Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS 
Journal of neurology  2013;260(8):2023-2032.
In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNβ)-1a in patients with relapsing–remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFNβ-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFNβ-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32–59 % relative to IFNβ-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNβ-1a in most (95 %) subgroups. In patients with high disease activity despite IFNβ treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNβ-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFNβ-1a across different subgroups of patients with RRMS.
PMCID: PMC3737385  PMID: 23632946
Multiple sclerosis; Randomized clinical trial; Fingolimod; Interferon-beta; MRI; Subgroup analysis
3.  Familial Hypobetalipoproteinemia-Induced Nonalcoholic Steatohepatitis 
Case Reports in Gastroenterology  2012;6(2):429-437.
Familial hypobetalipoproteinemia (FHBL) is a rare genetic disorder of lipid metabolism that is associated with abnormally low serum levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. It is an autosomal co-dominant disorder, and depending on zygosity, the clinical manifestations may vary from none to neurological, endocrine, hematological or liver dysfunction. Nonalcoholic fatty liver disease is common in persons with FHBL, however progression to nonalcoholic steatohepatitis is unusual. We describe here a patient with a novel APOB mutation, V703I, which appears to contribute to the severity of the FHBL phenotype. He had liver enzyme abnormalities, increased echogenicity of the liver consistent with steatosis, very low LDL cholesterol at 0.24 mmol/l (normal 1.8–3.5 mmol/l) and an extremely low apolipoprotein B level of 0.16 g/l (normal 0.6–1.2 g/l). APOB gene sequencing revealed him to be a compound heterozygote with two mutations (R463W and V703I). APOB R463W has previously been reported to cause FHBL. Genetic sequencing of his first-degree relatives identified the APOB V703I mutation in his normolipidemic brother and father and the APOB R463W mutation in his mother and sister, both of whom have very low LDL cholesterol levels. These results suggest that the APOB V703I mutation alone does not cause the FHBL phenotype. However, it is possible that it has a contributory role to a more aggressive phenotype in the presence of APOB R463W.
PMCID: PMC3398101  PMID: 22855658
Familial hypobetalipoproteinemia; Nonalcoholic steatohepatitis; APOB
4.  Lipid-bound apolipoproteins in tyrosyl radical-oxidized HDL stabilize ABCA1 like lipid-free apolipoprotein A-I 
BMC Biochemistry  2012;13:1.
ATP-binding cassette transporter A1 (ABCA1) mediates the lipidation of exchangeable apolipoproteins, the rate-limiting step in the formation of high density lipoproteins (HDL). We previously demonstrated that HDL oxidized ex vivo by peroxidase-generated tyrosyl radical (tyrosylated HDL, tyrHDL) increases the availability of cellular cholesterol for efflux and reduces the development of atherosclerosis when administered to apolipoprotein E-deficient mice as compared to treatment with control HDL.
In the current study we determined that tyrHDL requires functional ABCA1 for this enhanced activity. Like lipid-free apolipoprotein A-I (apoA-I), tyrHDL increases total and cell surface ABCA1, inhibits calpain-dependent and -independent proteolysis of ABCA1, and can be bound by cell surface ABCA1 in human skin fibroblasts. Additionally, tyrHDL apoproteins are susceptible to digestion by enteropeptidase like lipid-free apoA-I, but unlike lipid-bound apoA-I on HDL, which is resistant to proteolysis.
These results provide the first evidence that lipid-bound apolipoproteins on the surface of spherical HDL particles can behave like lipid-free apoA-I to increase ABCA1 protein levels and activity.
PMCID: PMC3292454  PMID: 22248050
5.  Prevalence of dyslipidemia in statin-treated patients in Canada: Results of the DYSlipidemia International Study (DYSIS) 
The Canadian Journal of Cardiology  2010;26(9):e330-e335.
Despite clear guideline recommendations, there is a growing body of evidence that there is suboptimal use of lipid-lowering treatment in Canadians.
To assess the prevalence and types of persistent lipid abnormalities in Canadian patients receiving statin therapy.
The present cross-sectional study recruited 2436 outpatients 45 years of age or older who were treated with statins by 232 physicians from 10 provinces; all underwent clinical examination and had their latest fasting lipid values while on statin therapy recorded.
The median patient age was 66 years (interquartile range [IQR] 58 to 74 years), 60% were men and 80% were in the high 10-year risk category. The median low-density lipoprotein cholesterol level was 2.0 mmol/L (IQR 1.6 mmol/L to 2.5 mmol/L) and the median total cholesterol/high-density lipoprotein cholesterol ratio was 3.4 mmol/L (IQR 2.8 mmol/L to 4.1 mmol/L). However, based on the 2006 Canadian Cardiovascular Society recommendations, 37% of all patients did not have a low-density lipoprotein cholesterol level at goal or intervention target level, including 45% of high-risk category patients. The majority of patients received atorvastatin (50%) or rosuvastatin (37%) but primarily at low-to-medium doses, and a minority (14%) received additional lipid-modifying therapies.
The present observational study highlights the need for more intensive treatment of lipid abnormalities, particularly among high-risk patients. Recognizing several important limitations related to the observational nature of the study, the findings suggest the possibility that, in addition to optimizing adherence, there remains an important need to titrate current statin therapy to higher doses and potentially use a combination of lipid-modifying treatments (once the statin dose has been truly maximized) to further bridge the gap between evidence-based medicine and current Canadian practice.
PMCID: PMC2989357  PMID: 21076724
Cholesterol; Dyslipidemia; Lipids
6.  Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study 
Severe hypertriglyceridemia (HTG) is one cause of acute pancreatitis, yet the level of plasma triglycerides likely to be responsible for inducing pancreatitis has not been clearly defined.
Methods and Results
A retrospective cohort study was conducted on patients presenting non-acutely to the Healthy Heart Program Lipid Clinic at St. Paul's Hospital with a TG level > 20 mM (1772 mg/dl) between 1986 and 2007. Ninety-five patients with TG > 20 mM at the time of referral were identified, in who follow up data was available for 84. Fifteen patients (15.8%), with a mean outpatient TG level of 38.1 mM, had a history of acute pancreatitis. Among 91 additional patients with less severe HTG, none had a history of pancreatitis when TG were between 10 and 20 mM. Among patients with TG > 20 mM on presentation, 8 (8.5%), with a mean TG level of 67.8 mM, exhibited eruptive xanthomata. A diet high in carbohydrates and fats (79%) and obesity (47.6%) were the two most frequent secondary causes of HTG at initial visit. By 2009, among patients with follow up data 53% exhibited either pre-diabetes or overt Type 2 diabetes mellitus. Upon referral only 23 patients (24%) were receiving a fibrate as either monotherapy or part of combination lipid-lowering therapy. Following initial assessment by a lipid specialist this rose to 84%, and remained at 67% at the last follow up visit.
These results suggest hypertriglyceridemia is unlikely to be the primary cause of acute pancreatitis unless TG levels are > 20 mM, that dysglycemia, a diet high in carbohydrates and fats, and obesity are the main secondary causes of HTG, and that fibrates are frequently overlooked as the drug of first choice for severe HTG.
PMCID: PMC3180406  PMID: 21906399
Hypertriglyceridemia; triglycerides; pancreatitis; dysglycemia; diabetes; fibrates
7.  2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations 
The Canadian Journal of Cardiology  2009;25(10):567-579.
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.
PMCID: PMC2782500  PMID: 19812802
Atherosclerosis; Cardiovascular risk factors; Cholesterol; Coronary artery disease; Dyslipidemia; Lipids; Secondary prevention
9.  Maintenance of improved lipid levels following attendance at a cardiovascular risk reduction clinic: a 10-year experience 
Vascular Health and Risk Management  2008;4(5):1127-1135.
Specialty cardiovascular risk reduction clinics (CRRC) increase the proportion of patients attaining recommended lipid targets; however, it is not known if the benefits are sustained after discharge. We evaluated the impact of a CRRC on lipid levels and assessed the long-term effect of a CRRC in maintaining improved lipid levels following discharge.
The medical records of consecutive dyslipidemic patients discharged ×6 months from a tertiary hospital CRRC from January 1991 to January 2001 were retrospectively reviewed. The primary outcome was the change in patients’ lipid levels between the final CRRC visit and the most recent primary care follow-up. A worst-case analysis was conducted to evaluate the potential impact of the patients in whom the follow-up lipid profiles post-discharge from the CRRC were not obtained.
Within the CRRC (median follow-up = 1.28 years in 1064 patients), we observed statistically significant improvements in all lipid parameters. In the 411 patients for whom post-discharge lipid profiles were available (median follow-up = 2.41 years), there were no significant differences observed in low-density lipoprotein-cholesterol, total cholesterol (TC), or triglycerides since CRRC discharge; however, there were small improvements in high-density lipoprotein-cholesterol (HDL-C) and TC:HDL ratio (p < 0.05 for both). The unadjusted worst-case analysis (653 patients with no follow-up lipid profiles) demonstrated statistically significant worsening of all lipid parameters between CRRC discharge and the most recent follow-up. However, when the change in lipid parameters between the baseline and the most recent follow-up was assessed in this analysis, the changes in all lipid parameters were significantly improved (p < 0.05).
This study demonstrates that a CRRC can improve lipid levels and suggests that these benefits are sustained once patients are returned to the care of their primary physician.
PMCID: PMC2605345  PMID: 19183763
cardiovascular risk factors; dyslipidemia; outcomes; pharmacotherapy; secondary prevention
10.  Cytokine Changes During Interferon-beta Therapy in Multiple Sclerosis: Correlations with Interferon dose and MRI response 
Journal of neuroimmunology  2007;185(1-2):168-174.
We investigated serum (IL-10 and IL-12p70) and cellular cytokine levels (IL-10, IL-12p40, IL-12p70, IFN-γ) in stimulated PBMC over 24 weeks in 15 Relapsing Remitting Multiple Sclerosis (MS) patients randomized to receive once-weekly (qw) IFN-β-1a 30 ug intramuscularly (IM) (n=8) or three-times-weekly (tiw) IFN-β-1a 44 ug subcutaneously (SC) (n=7). Overall, IFN-β treatment increased cellular IL-10 (p<0.01) levels and the ratios of cellular IL-10/IL-12p40 (p<0.01) and IL-10/IL-12p70 (p<0.02) while cellular IFN-γ levels were reduced (P<0.01). Serum IL-10 levels were decreased in non-responders to therapy based on MRI-defined criteria (p<0.01) but did not change in responders over the course of treatment. In addition, non-responders demonstrated a decrease in serum IL-10/IL-12p70 ratio (p=0.031) and a decrease in cellular IL-12p70 (p<0.02). A decrease in cellular IFN-γ was observed in responders (p=0.013). This is the first study that compares cytokine changes between the two IFN-β regimes and demonstrates that serum IL-10 levels decrease in those patients who continue to have active MRI lesions while on interferon-beta therapy.
PMCID: PMC1894687  PMID: 17328965
multiple sclerosis; interferon-beta; interleukin-10; interleukin-12; interferon-gamma; biomarker
11.  The clinical effect and tolerability of ezetimibe in high-risk patients managed in a specialty cardiovascular risk reduction clinic 
The Canadian Journal of Cardiology  2006;22(11):939-945.
Ezetimibe (EZ) is a selective cholesterol absorption inhibitor approved for use in Canada. The effect and tolerability of EZ among patients was evaluated in the clinical setting of a specialty cardiovascular risk reduction clinic at the University of Alberta Hospital, Edmonton, Alberta.
All patients 18 years of age or older who were prescribed EZ were included, unless they failed to take EZ for a minimum of two weeks, did not have baseline and on-EZ low-density lipoprotein cholesterol (LDL-C) levels, or had concomitant lipid-lowering drugs or dosages changed within one month of starting EZ.
Eighty-four patients (mean age 57.9 years) were included. By Framingham risk calculation, 71.4% were found to be high-risk patients, 13.1% moderate-risk patients and 15.5% low-risk patients; 66.7% of patients had prior cardiovascular events. On EZ, the mean reductions were: total cholesterol level 1.11 mmol/L (16.5%); LDL-C level 1.01 mmol/L (22.3%); high-density lipoprotein cholesterol level 0.06 mmol/L (4.6%); and ratio of total cholesterol level to high-density lipoprotein cholesterol level 0.68 mmol/L (12.8%); all were statistically significant (P<0.001). Results were similar when stratified by primary (n=28) versus secondary (n=56) prevention. Patients on EZ monotherapy (n=34) had mean LDL-C reductions of 1.03 mmol/L (20.5%) compared with 1.19 mmol/L (30.1%) or 0.95 mmol/L (22.5%), where EZ was added to low-dose or high-dose statins (P<0.01 for all). On EZ, 30 patients (35.7%) achieved previously unattainable target LDL-C levels. Four patients discontinued the drug due to side effects.
EZ is safe and effective in high-risk patients treated in the clinical setting of a cardiovascular risk reduction clinic. A mean LDL-C reduction of 1 mmol/L (20% to 30%) in all patient subgroups is consistent with previous clinical trial results. The significant reduction in LDL-C (mean 22.5%) observed in the EZ plus high-dose statin subgroup provides clinical evidence for use of this medication beyond published studies.
PMCID: PMC2570239  PMID: 16971979
Cholesterol; Ezetimibe; Hyperlipoproteinemia; Lipids; Risk factors
12.  Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3) 
Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition.
We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol.
The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable.
Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.
PMCID: PMC1368963  PMID: 16412238
13.  Cerebral cholesterol granuloma in homozygous familial hypercholesterolemia 
Familial hypercholesterolemia (FH) is characterized by the accumulation of excess cholesterol in tissues including the artery wall and tendons. We describe a patient with homozygous FH who presented with asymptomatic cholesterol granuloma of the brain. The patient's plasma low-density lipoprotein cholesterol level was remarkably responsive to combination hypolipidemic therapy with statin plus ezetimibe. This case illustrates another potential complication of whole-body cholesterol excess and underscores the differences in phenotype and in response to therapy among patients with FH.
PMCID: PMC548411  PMID: 15710941
14.  Recurrent Otitis Media in Children 
Canadian Medical Association Journal  1957;77(12):1121-1122.
PMCID: PMC1824318  PMID: 20325609

Results 1-14 (14)