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

BACKGROUND: Glycosylation 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. METHODS: Nuclear 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). RESULTS: GlycA 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. CONCLUSIONS: High 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.

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.

Underappreciated opportunities for high-density lipoprotein particles in risk stratification and potential targets of therapy.

The inverse relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and coronary heart disease risk is well established. As a result, in recent years there have been significant resources focused on identifying therapies that raise HDL-C and ultimately reduce cardiovascular events. Unfortunately, a number of trials aimed at increasing HDL-C have failed to show improved outcomes, and hence, have cast doubt on the importance of HDL-C as a therapeutic target. HDL-C, however, is only one measure of HDL. HDL levels can also been estimated by quantifying apolipoprotein A-I (apoA-I) levels using enzyme immunoassay or by measuring HDL particle number (HDL-P) using nuclear magnetic resonance spectroscopy (NMR) or ion mobility. While these surrogate measures are correlated, they are not comparable. Lipoprotein-altering therapies have been shown to have different effects on HDL-C, apoA-I and HDL-P and several studies have demonstrated that HDL-P is a stronger predictor of coronary heart disease risk than HDL-C and/or apoA-I. This paper will review available evidence supporting the use of HDL-P as the biomarker of choice to assess the contribution of HDL to cardiovascular risk and as the primary goal of HDL-raising therapies.

Lipoprotein particle concentrations in children and adults following Kawasaki disease.

OBJECTIVE: To test the hypothesis that children and adults with a history of Kawasaki disease (KD) are more likely to have abnormal lipoprotein particle profiles that could place them at increased risk for developing atherosclerosis later in life. STUDY DESIGN: Fasting serum samples were obtained from 192 children and 63 adults with history of KD and 90 age-similar healthy controls. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy (LipoScience Inc, Raleigh, North Carolina), and serum was assayed for total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) cholesterol (HDL-C). Low-density lipoprotein (LDL) cholesterol was estimated using the Friedewald formula. Data were analyzed in a least-square means model, with adjustment for age and sex and with the use of Holm correction for multiple comparisons. RESULTS: Compared with respective control groups, both adult and pediatric subjects with KD had significantly lower mean very low-density lipoprotein-chylomicron particles, intermediate-density lipoproteins, triglycerides, and TC concentrations. Pediatric subjects with KD had significantly lower LDL particle and LDL cholesterol concentrations and lower mean TC/HDL-C ratio (P < .001). In contrast, the adult subjects with KD had significantly lower HDL particle, small HDL particle, and HDL-C concentrations (P < .001), but HDL-C was within normal range. CONCLUSIONS: Nuclear magnetic resonance lipoprotein particle analysis suggests that pediatric and adult subjects with KD, regardless of their aneurysm status, are no more likely than age-similar, healthy controls to have lipid patterns associated with increased risk of atherosclerosis.

Evaluation of low-density lipoprotein particle number distribution in patients with type 2 diabetes mellitus with low-density lipoprotein cholesterol <50 mg/dl and non-high-density lipoprotein cholesterol <80 mg/dl.

Many patients with type 2 diabetes mellitus (T2DM) have relatively normal levels of low-density lipoprotein (LDL) cholesterol yet have increased risk for cardiovascular events. Distribution of lipoprotein subclasses in patients with T2DM who have achieved very low levels of LDL cholesterol (<50 mg/dl) or non-high-density lipoprotein (HDL) cholesterol (<80 mg/dl) have not been extensively examined. The aim of this study was to assess variations in lipoprotein particle concentration in patients with diabetes with "very low" LDL cholesterol and non-HDL cholesterol levels to elucidate the drivers of residual cardiovascular risk. Data were selected from a single large clinical laboratory database. Cases were patients with T2DM diagnosis codes (International Classification of Diseases, Ninth Revision, codes 250 to 250.93). Lipoprotein particle concentrations were analyzed using nuclear magnetic resonance spectroscopy. The Friedewald equation was used to calculate LDL cholesterol. Among the 1,970 patients with T2DM, the mean age was 61 years, and approximately 51% were men. At LDL cholesterol concentrations <50 mg/dl (triglyceride <150 mg/dl and HDL cholesterol >40 mg/dl), 16% had LDL particle concentrations <500 nmol/L, 70% had concentrations of 500 to 1,000 nmol/L, and 14% had concentrations >1,001 nmol/L. At non-HDL cholesterol levels <80 mg/dl, 8% had LDL particle concentrations <500 nmol/L, 67% had concentrations of 500 to 1,000 nmol/L, and 25% had concentrations >1,001 nmol/L. In conclusion, despite attainment of LDL cholesterol <50 mg/dl or non-HDL cholesterol <80 mg/dl, patients with diabetes exhibited significant variation in LDL particle levels, with most having LDL particle concentrations >500 nmol/L, suggesting the persistence of potential residual coronary heart disease risk.

Opportunities for using lipoprotein subclass profile by nuclear magnetic resonance spectroscopy in assessing insulin resistance and diabetes prediction.

The incidence of type 2 diabetes mellitus (T2DM) has reached epidemic levels, and current trends indicate that its prevalence will continue to rise. The development of T2DM can be delayed by several years, and may even be prevented, by identifying individuals at risk for T2DM and treating them with lifestyle modification and/or pharmacological therapies. There are a number of methods available for assessing the insulin resistance (IR) that characterizes, and is the precursor to, T2DM. However, current clinical methods for assessing IR, based on measures of plasma glucose and/or insulin are either laborious and time-consuming or show a low specificity. IR manifests its earliest measurable abnormalities through changes in lipoproteins, and thus we propose that by examining lipoprotein subclass profile, it may be possible to alert physicians and patients to a heightened risk of developing diabetes. This will allow us to institute appropriate lifestyle changes and treatment potentially to delay the onset or possibly prevent the progression to diabetes.

Adolescent diet and metabolic syndrome in young women: results of the Dietary Intervention Study in Children (DISC) follow-up study.

CONTEXT: Childhood diet is hypothesized to influence development of chronic disease in adulthood. OBJECTIVE: Our objective was to evaluate the long-term effects of a dietary intervention to reduce fat and increase fiber intake during childhood and adolescence on the prevalence of metabolic syndrome in young adult women. DESIGN: A follow-up study was conducted in 2006-2008, 9 yr after termination of the Dietary Intervention Study in Children (DISC). SETTING: The study took place at six DISC clinical centers in the United States. PARTICIPANTS: A total of 230 (76%) DISC female participants who were 25-29 yr old and had not been pregnant or breastfeeding in the previous 3 months participated in the follow-up study. INTERVENTION: There was no intervention between the end of the DISC trial and the follow-up visit. MAIN OUTCOME MEASURE: Metabolic syndrome was the primary study endpoint planned before data collection and was hypothesized to be less common in the intervention group participants. RESULTS: Metabolic syndrome was uncommon, and its prevalence did not differ by treatment group. However, after adjustment for nondietary variables, mean systolic blood pressures of intervention and control group participants were 107.7 and 110.0 mm Hg, respectively (P = 0.03), whereas mean fasting plasma glucose levels were 87.0 and 89.1 mg/dl, respectively (P = 0.01). Intervention group participants also had lower concentrations of large very-low-density lipoprotein particles, a marker of hepatic insulin resistance, compared with control group participants. Adjustment for current diet did not materially alter results. CONCLUSION: Consumption of a diet lower in fat and higher in fiber during childhood and adolescence may benefit glycemic control and blood pressure long term.

Underappreciated opportunities for low-density lipoprotein management in patients with cardiometabolic residual risk.

Prospective studies of coronary heart disease patients with disorders of insulin resistance, metabolic syndrome (MetSyn) and type 2 diabetes (T2DM), have shown that these patients usually display high levels of low-density lipoprotein particles (LDL-P) and low levels of high-density lipoprotein particles (HDL-P). In multiple prospective studies, high levels of LDL-P are more predictive of CHD risk than low-density lipoprotein cholesterol (LDL-C). The conventional goal of lipid lowering treatment is to lower LDL-C levels; however LDL-C is unrelated to the severity of insulin resistance. Among high cardiometabolic risk patients with LDL-C <100 mg/dL, about two-thirds of patients have a high LDL-P (>1000 nmol/L) despite this "optimal" level of LDL-C. For high cardiometabolic risk patients, LDL-P should be considered a primary goal of therapy due to its stronger association with cardiovascular risk. Further, we propose that certain lipid-altering therapies may be particularly useful in reducing cardiovascular events in statin-treated patients, not simply due to their improvement in LDL-C goal attainment, but due to their effects on lowering the number of low-density lipoprotein particles (LDL-P).

A randomized trial of an acid-peptic disease management program in a managed care environment.

OBJECTIVE: To study the effectiveness of a disease management program for patients with acid-related disorders. STUDY DESIGN: A cluster-randomized clinical trial of 406 patients comparing a disease management program with "usual practice." PATIENTS AND METHODS: Enrolled patients included those presenting with new dyspepsia and chronic users of antisecretory drugs in 8 geographically separate physician offices associated with the Orlando Health Care Group. There were 35 providers in the intervention group and 48 in the control group. The disease management program included evidence-based practice guidelines implemented by using physician champions, academic detailing, and multidisciplinary teams. Processes of care, patient symptoms, quality of life, costs, and work days lost were measured 6 months after patient enrollment. RESULTS: Compared with usual practice, disease management was associated with improvements in Helicobacter pylori testing (61% vs 9%; P = .001), use of recommended H pylori treatment regimens (96% vs 10%; P = .001), and discontinuation rates of proton pump therapy after treatment (70% vs 36%; P = .04). There were few differences in patient quality of life or symptoms between the 2 study groups. Disease management resulted in fewer days of antisecretory therapy (71.7 vs 88.1 days; P = .02) but no difference in total costs. CONCLUSION: This disease management program for patients with acid-related disorders led to improved processes of care. The effectiveness of such a program in other settings requires further study.