Low-Density Lipoprotein Subfractionation: What Is the Role of the Lab When Reporting Discrepant Results?

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S8-S9
Author(s):  
Nicholas E Larkey ◽  
Leslie J Donato ◽  
Allan S Jaffe ◽  
Jeffrey W Meeusen
Keyword(s):  
Coronary Artery ◽  
High Risk ◽  
Clinical Decision Making ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Risk ◽  
Lipid Lowering ◽  
Low Density ◽  
Small Dense Ldl ◽  
Increased Risk

Abstract Plasma concentrations of low-density-lipoprotein cholesterol (LDL-C) are directly associated with risk for coronary artery disease (CAD). Multisociety guidelines define LDL-C>160mg/dL as a risk factor for CAD and LDL-C>190mg/dL as an indication for lipid lowering medication, regardless of other clinical factors. Subfractionation of LDL according to size (LDL-s) enables differentiation between two LDL phenotypes: large-buoyant LDL and small-dense LDL. The small-dense LDL phenotype reportedly conveys increased risk for CAD. Major societies do not recommend LDL subfractions be used for clinical decision making and most payers do not cover LDL subfraction testing. Despite these restrictions, LDL subfraction is routinely requested by clinicians. Nuclear magnetic resonance (NMR) spectroscopy measures LDL-C and LDL-s. Following inquiries regarding interpretation of conflicting LDL-C and LDL-s results, we investigated associations between LDL-C and LDL-s measured by NMR in order to determine how often they provide contradicting or additive information. Verification of NMR LDL-C accuracy was confirmed by ß-quantification in a subset of patient samples (n=250). The average bias was -4.5mg/dL and the correlation coefficient was 0.92. High-risk was defined as LDL-C>160mg/dL or LDL-s<20.5 nm (small-dense LDL); and low-risk was defined as LDL-C<70mg/dL or LDL-s>20.5nm (large-buoyant LDL). In 26,710 clinical NMR analyses, the median LDL-C was 94.0mg/dL (range:5-436mg/dL) with median LDL-s of 20.8 nm (range:19.4–23.0nm). LDL-s moderately correlated with LDL-C (Ï#129;=0.51;p<0.01). Small-dense-LDL was identified in only 18% (407/2,191) of patients with elevated LDL-C (>160mg/dL) and was more common (73.2% of 6,093) in patients with low LDL-C (<70mg/dL;p<0.001). Associations with CAD were investigated among patients without cholesterol-lowering medication treatment referred for angiography (n=356). CAD (defined as stenosis >50% in one or more coronary artery) was diagnosed in 14% (1/7) of subjects with low LDL-C (<70mg/dL) compared to 59% (47/80) of subjects with elevated LDL-C (p=0.01). When stratifying by LDL-s, CAD was diagnosed in 50% (57/115) of subjects with small-dense LDL compared to 43% (104/241) of subjects with large-buoyant LDL (p=0.2). Small-dense LDL was identified in only 33% (26/80) of cases with elevated LDL-C. Limiting to subjects with elevated LDL-C, CAD was diagnosed in 50% (13/26) of subjects with concordant (high-risk) small-dense LDL compared to 61% (33/54) of subjects with discordant (low-risk) large-buoyant LDL (LDL-s>20.5nm) (p=0.3). Our data confirm that LDL-s subfraction measured by NMR is reported discordantly in most cases when LDL-C is unequivocally high or low. Furthermore, CAD diagnosis was significantly associated with LDL-C, but not with LDL-s. Our data also show that in discrepant samples, elevated LDL-C correlates better with disease state compared to LDL-s. Therefore, LDL-s should not be used to justify treatment decisions in patients with elevated LDL-C. Laboratories should consider carefully whether or not to report LDL-s when it is known that misleading and discordant values will be reported in a majority of cases.

scholarly journals Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

2021 ◽  
Vol 23 (12) ◽  
Author(s):  
Angela Pirillo ◽  
Alberico L. Catapano ◽  
Giuseppe D. Norata
Keyword(s):  
Monoclonal Antibodies ◽  
High Risk ◽  
Familial Hypercholesterolemia ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Genetic Defect ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Low Density ◽  
Premature Cardiovascular Disease

Abstract Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.

Cardiovascular event rates increase after each recurrence and associate with poor statin adherence

2020 ◽  
pp. 204748732090433 ◽  
Author(s):  
Mariann I Lassenius ◽  
Iiro Toppila ◽  
Susanne Bergius ◽  
Julia Perttilä ◽  
KE Juhani Airaksinen ◽  
...  
Keyword(s):  
Cardiovascular Event ◽  
Cardiovascular Events ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Increased Risk ◽  
Event Rates

Aims The study evaluated the quality of cardiovascular prevention in real-world clinical practice. The recurrence of up to five cardiovascular events was assessed, as data on recurrence beyond the first event and interindividual variations in event rates past the second event have been sparse. Low-density lipoprotein cholesterol concentrations and lipid-lowering therapy use were investigated. Methods This retrospective register-based study included adult patients with an incident cardiovascular event between 2004 and 2016 treated in the hospital district of southwest Finland. Patients were followed for consecutive cardiovascular events or cardiovascular death, low-density lipoprotein cholesterol and statin purchases. The timing of event recurrence was evaluated, and predictive factors were assessed. Results A wide interindividual variation in cardiovascular event recurrence was observed, each additional event caused an increased risk, the median time of recurrence decreased from 7 to one year for the second and fifth event. Event rates increased correspondingly from 12 to 43/100 patient-years and were most pronounced in the first years following the previous event. The low-density lipoprotein cholesterol goal (<1.8 mmol/l) was reached by 18% in the year after the event and statin underuse was associated with an increased risk of recurrence. Six months after the index event high intensity statins were used by only 22% of the cohort. Conclusion The study provides new perspectives on individual risk assessment showing that event rates are not stable for all patients but increase 1.2–1.9-fold per consecutive event. The underuse of statins and poor adherence support the identification of these patients for intensified multifactorial preventive measures.

scholarly journals Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study

BMJ ◽  
2020 ◽  
pp. m4266
Author(s):  
Camilla Ditlev Lindhardt Johannesen ◽  
Anne Langsted ◽  
Martin Bødtker Mortensen ◽  
Børge Grønne Nordestgaard
Keyword(s):  
Cohort Study ◽  
General Population ◽  
Prospective Cohort ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Low Density ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Specific Mortality

Abstract Objective To determine the association between levels of low density lipoprotein cholesterol (LDL-C) and all cause mortality, and the concentration of LDL-C associated with the lowest risk of all cause mortality in the general population. Design Prospective cohort study. Setting Denmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years. Participants Individuals randomly selected from the national Danish Civil Registration System. Main outcome measures Baseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (cardiovascular, cancer, and other mortality). Results Among 108 243 individuals aged 20-100, 11 376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted hazard ratio for all cause mortality was 1.25 (95% confidence interval 1.15 to 1.36) for individuals with LDL-C concentrations of less than 1.8 mmol/L (<70 mg/dL; 1st-5th centiles) and 1.15 (1.05 to 1.27) for LDL-C concentrations of more than 4.8 mmol/L (>189 mg/dL; 96th-100th centiles). The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction. Conclusions In the general population, low and high levels of LDL-C were associated with an increased risk of all cause mortality, and the lowest risk of all cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL).

scholarly journals Lower levels of low-density lipoprotein cholesterol are associated with lower prevalence of thin-cap fibroatheroma in statin-treated patients with coronary artery disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Hashimoto ◽  
Y Minami ◽  
K Asakura ◽  
M Katamine ◽  
A Kato ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
High Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lower Prevalence ◽  
Low Density Lipoprotein Cholesterol ◽  
Risk Patients ◽  
Artery Disease

Abstract Background Lowering low-density lipoprotein cholesterol (LDL-C) with statins slows progression of atherosclerotic plaques and reduces cardiovascular events. The 2019 European Society of Cardiology guideline for the management of dyslipidaemias recommends the absolute LDL-C treatment target as &lt;55mg/dL for very high-risk patients, &lt;70 mg/dL for high-risk patients and &lt;100 mg/dL for moderate-risk patients. However, the difference in plaque composition of coronary lesions according to these LDL-C levels remains to be elucidated. Purpose To investigate plaque morphologies according to LDL-C levels in statin-treated patients with coronary artery disease (CAD). Methods A total of 685 consecutive statin-treated patients with CAD, who underwent optical coherence tomography (OCT) imaging of culprit lesions were enrolled. The prevalence of vulnerable compositions in culprit plaques evaluated by OCT was compared among the groups of patients classified by LDL-C levels (&lt;55, 55–70, 70–100, ≥100 mg/dL). Results LDL-C levels &lt;55 mg/dL, &lt;70 mg/dL and &lt;100 mg/dL were observed in 6.3%, 21.8% and 63.9% of patients, respectively. The prevalence of thin-cap fibroatheroma was significantly different among the groups (P=0.014, Figure) with a trend toward lower prevalence in the lower two LDL-C groups than in the higher two LDL-C groups. A gradient with lower prevalence of thrombus in lower LDL-C groups was observed, although the statistical significance was not demonstrated (Figure). There was no significant difference in the prevalence of macrophage or cholesterol crystal among the groups. Conclusions Lower LDL-C level was associated with a trend toward lower prevalence of thin-cap fibroatheroma and thrombus in statin-treated patients with CAD. Funding Acknowledgement Type of funding source: None

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