Ray Pourfarzib

Effect of PCSK9 Inhibition by Alirocumab on Lipoprotein Particle Concentrations Determined by Nuclear Magnetic Resonance Spectroscopy

Background In patients with discordance between low‐density lipoprotein (LDL) cholesterol and LDL particle (LDL‐P) concentrations, cardiovascular risk more closely correlates with LDL−P. Methods and Results We investigated the effect of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentration and size in hypercholesterolemic patients, using nuclear magnetic resonance spectroscopy. Plasma samples were collected from patients receiving alirocumab 150 mg every 2 weeks (n=26) or placebo (n=31) during a phase II, double‐blind, placebo‐controlled trial in patients (LDL cholesterol ≥100 mg/dL) on a stable atorvastatin dose. In this post hoc analysis, percentage change in concentrations of LDL−P, very‐low‐density lipoprotein particles, and high‐density lipoprotein particles from baseline to week 12 was determined by nuclear magnetic resonance. Alirocumab significantly reduced mean concentrations of total LDL‐P (−63.3% versus −1.0% with placebo) and large (−71.3% versus −21.8%) and small (−54.0% versus +17.8%) LDL‐P subfractions and total very‐low‐density lipoprotein particle concentrations (−36.4% versus +33.4%; all P<0.01). Total high‐density lipoprotein particles increased with alirocumab (+11.2% versus +1.4% with placebo; P<0.01). There were greater increases in large (44.6%) versus medium (17.7%) or small high‐density lipoprotein particles (2.8%) with alirocumab. LDL‐P size remained relatively unchanged in both groups; however, very‐low‐density and high‐density lipoprotein particle sizes increased to a significantly greater extent with alirocumab. Conclusions Alirocumab significantly reduced LDL‐C and LDL‐P concentrations in hypercholesterolemic patients receiving stable atorvastatin therapy. These findings may be of particular relevance to patients with discordant LDL‐C and LDL‐P concentrations. Clinical Trial Registration URL: https://clinicaltrials.gov. Unique identifier: NCT01288443.

Differences in GlycA and lipoprotein particle parameters may help distinguish acute kawasaki disease from other febrile illnesses in children

BackgroundGlycosylation patterns of serum proteins, such as α1-acid glycoprotein, are modified during an acute phase reaction. The response of acute Kawasaki disease (KD) patients to IVIG treatment has been linked to sialic acid levels on native IgG, suggesting that protein glycosylation patterns vary during the immune response in acute KD. Additionally, the distribution and function of lipoprotein particles are altered during inflammation. Therefore, the aim of this study was to explore the potential for GlycA, a marker of protein glycosylation, and the lipoprotein particle profile to distinguish pediatric patients with acute KD from those with other febrile illnesses.MethodsNuclear magnetic resonance was used to quantify GlycA and lipoprotein particle classes and subclasses in pediatric subjects with acute KD (n = 75), post-treatment subacute (n = 36) and convalescent (n = 63) KD, as well as febrile controls (n = 48), and age-similar healthy controls (n = 48).ResultsGlycA was elevated in acute KD subjects compared to febrile controls with bacterial or viral infections, IVIG-treated subacute and convalescent KD subjects, and healthy children (P <0.0001). Acute KD subjects had increased total and small low density lipoprotein particle numbers (LDL-P) (P <0.0001) and decreased total high density lipoprotein particle number (HDL-P) (P <0.0001) compared to febrile controls. Consequently, the ratio of LDL-P to HDL-P was higher in acute KD subjects than all groups tested (P <0.0001). While GlycA, CRP, erythrocyte sedimentation rate, LDL-P and LDL-P/HDL-P ratio were able to distinguish patients with KD from those with other febrile illnesses (AUC = 0.789–0.884), the combinations of GlycA and LDL-P (AUC = 0.909) or GlycA and the LDL-P/HDL-P ratio (AUC = 0.910) were best at discerning KD in patients 6–10 days after illness onset.ConclusionsHigh levels of GlycA confirm enhanced protein glycosylation as part of the acute phase response in KD patients. When combined with common laboratory tests and clinical characteristics, GlycA and NMR-measured lipoprotein particle parameters may be useful for distinguishing acute KD from bacterial or viral illnesses in pediatric patients.

DISCORDANCE IN LOW-DENSITY LIPOPROTEIN PARTICLE NUMBER (LDL-P) AND APOLIPOPROTEIN B (APO B) LEVEL

Many subjects with relatively normal levels of LDL cholesterol have increased numbers of atherogenic lipoproteins, hence exhibiting discordance. There are few data comparing the relationship between an individuals LDL-P and Apo B levels and whether discordance exists between these values. To

Relationship between plasma apolipoprotein B concentrations and LDL particle number

Many subjects with relatively normal, or even optimal, levels of low-density lipoprotein cholesterol (LDL-C) have increased atherogenic lipoprotein particle concentrations (apolipoprotein B (apoB) and LDL particle number (LDL-P) determined by nuclear magnetic resonance spec- troscopy (NMR)). Numerous analyses have demonstrated that apoB and LDL-P predict the risk of future cardiovascular events more robustly than LDL-C, as estimated using the Friedewald equation. Little is known about the relationship between an individuals apoB and LDL-P level, and whether the relationship is comparable at different levels of LDL-C. The aim of this study was to examine the correlation between plasma apoB and LDL-P levels and specifically to evaluate the heterogeneity of LDL-P at low levels of apoB (, the 20th population percentile (78 mg/dL)). Data were derived from a group of consecutive patients added to a large, single laboratory database (LipoScience, Inc.) during a 1-week period in which a standard lipid profile, apoB, and LDL-P levels were available. When risk categories were assigned to the subjects using the Framingham Offspring Studys population percentiles for apoB and LDL-P, there was good agreement between the two measures when LDL-C levels were high (

Impact of a Paleolithic Diet on Modifiable Cardiovascular Risk Factors

160 mg/dL). However, among individuals with low LDL-C and apoB, NMR analysis could identify a subgroup of individuals with potentially

NMR-BASED LIPOPROTEIN PARTICLE PROFILING IDENTIFIES NOVEL SIGNATURES FOR CARDIOVASCULAR DISEASE

Mean Age (years) 54.2 6 9.6 Weight (lbs) 200 6 50 188 6 47 BMI (kg/m2) 33.1 6 7.5 31.1 6 7.5 Fasting glucose (mg/dL) 92 6 9 93 6 10 DBP (mmHg) 82 6 11 76 6 10* Trigylcerides (mg/dL) 102 6 60 78 6 40* HDL cholesterol (mg/dL) 64 6 14 62 6 13 HDL particle number (umol/L) 36.2 6 6.7 33.4 6 3* LDL cholesterol (mg/dL) 125 6 33 124 6 36 LDL particle number (nmol/L) 1464 6 376 1429 6 389 VLDL particle number (nmol/L) 52 6 37 42 6 25*

Lipoprotein Particle Concentrations in Children and Adults following Kawasaki Disease

The standard lipid panel routinely performed for cardiovascular risk assessment measures the cholesterol and triglyceride content of lipoproteins. Lipoprotein particle concentrations measured by NMR spectroscopy more strongly associate with coronary artery disease (CAD) risk. We hypothesized that