scholarly journals Elevated Lipoprotein(a) Does Not Cause Low-Grade Inflammation Despite Causal Association With Aortic Valve Stenosis and Myocardial Infarction: A Study of 100 578 Individuals from the General Population

2015 ◽  
Vol 100 (7) ◽  
pp. 2690-2699 ◽  
Author(s):  
Anne Langsted ◽  
Anette Varbo ◽  
Pia R. Kamstrup ◽  
Børge G. Nordestgaard
2016 ◽  
Vol 101 (9) ◽  
pp. 3281-3287 ◽  
Author(s):  
Anne Langsted ◽  
Børge G. Nordestgaard ◽  
Marianne Benn ◽  
Anne Tybjærg-Hansen ◽  
Pia R. Kamstrup

Abstract Context: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. Objective: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. Design: We used two prospective cohort studies of the general population and one patient-based cohort. Setting: Cohort studies selected at random individuals of Danish descent. Participants: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. Main outcome measures: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. Results: Median (interquartile range) lipoprotein(a) levels were 10 (5–30) mg/dl for PCSK9 R46L noncarriers, 9 (4–32) mg/dl for heterozygotes, and 8 (4–42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101–147) mg/dl, 104 (85–132) mg/dl, and 97 (85–128) mg/dl, respectively (trend P = 2 × 10−52). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44–0.95) for aortic valve stenosis, 0.77 (0.65–0.92) for myocardial infarction, and 0.76 (0.64–0.89) for aortic valve stenosis or myocardial infarction. Conclusions: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.


2017 ◽  
Vol 102 (9) ◽  
pp. 3390-3399 ◽  
Author(s):  
Leonard Kritharides ◽  
Børge G Nordestgaard ◽  
Anne Tybjærg-Hansen ◽  
Pia R Kamstrup ◽  
Shoaib Afzal

Abstract Context APOE ε2/3/4 genotypes affect plasma lipoprotein(a); however, the effects of APOE genotypes on the prediction of myocardial infarction and aortic valve stenosis by lipoprotein(a) are unknown. Objective We tested the hypothesis that APOEε2/3/4 genotype affects plasma lipoprotein(a), the contribution of plasma apoE levels to this association as well as the associated risk of myocardial infarction and aortic valve stenosis. Design and Outcome Measures In 46,615 individuals from the general population, we examined plasma lipoprotein(a), APOE ε2/3/4, and incidence of myocardial infarction (n = 1807) and aortic valve stenosis (n = 345) over 37 years of follow-up (range: 0.3 to 38 years). Results Compared with ε33, age- and sex-adjusted lipoprotein(a) concentrations were lower by 15% in ε23, by 24% in ε24, and by 36% in ε22; adjusted for plasma apolipoprotein E, corresponding values were 22%, 28%, and 62%. These reductions were independent of LPA genotypes. Compared with ε2 carriers with lipoprotein(a) ≤50 mg/dL, the hazard ratio for myocardial infarction was 1.26 (95% confidence interval: 1.06 to 1.49) for ε2 noncarriers with lipoprotein(a) ≤50 mg/dL, 1.68 (1.21 to 2.32) for ε2 carriers with lipoprotein(a) >50 mg/dL, and 1.92 (1.59 to 2.32) for ε2 noncarriers with lipoprotein(a) >50 mg/dL (interaction, P = 0.57); corresponding values for aortic valve stenosis were 1.05 (0.74 to 1.51), 1.49 (0.72 to 3.08), and 2.04 (1.46 to 2.26) (interaction, P = 0.50). Further adjustment for APOE ε2/3/4 genotype had minimal influence on these risk estimates. Conclusions APOE ε2 is a strong genetic determinant of low lipoprotein(a) concentrations but does not modify the causal association of lipoprotein(a) with myocardial infarction or aortic valve stenosis.


2014 ◽  
Vol 63 (5) ◽  
pp. 470-477 ◽  
Author(s):  
Pia R. Kamstrup ◽  
Anne Tybjærg-Hansen ◽  
Børge G. Nordestgaard

2013 ◽  
Vol 34 (suppl 1) ◽  
pp. 1814-1814 ◽  
Author(s):  
P. R. Kamstrup ◽  
A. Tybjaerg-Hansen ◽  
B. G. Nordestgaard

Author(s):  
Gloria Santangelo ◽  
Andrea Faggiano ◽  
Nicola Bernardi ◽  
Stefano Carugo ◽  
Antonella Giammanco ◽  
...  

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
◽  
Heli Julkunen ◽  
Anna Cichońska ◽  
P Eline Slagboom ◽  
Peter Würtz

Biomarkers of low-grade inflammation have been associated with susceptibility to a severe infectious disease course, even when measured prior to disease onset. We investigated whether metabolic biomarkers measured by nuclear magnetic resonance (NMR) spectroscopy could be associated with susceptibility to severe pneumonia (2507 hospitalised or fatal cases) and severe COVID-19 (652 hospitalised cases) in 105,146 generally healthy individuals from UK Biobank, with blood samples collected 2007–2010. The overall signature of metabolic biomarker associations was similar for the risk of severe pneumonia and severe COVID-19. A multi-biomarker score, comprised of 25 proteins, fatty acids, amino acids and lipids, was associated equally strongly with enhanced susceptibility to severe COVID-19 (odds ratio 2.9 [95%CI 2.1–3.8] for highest vs lowest quintile) and severe pneumonia events occurring 7–11 years after blood sampling (2.6 [1.7–3.9]). However, the risk for severe pneumonia occurring during the first 2 years after blood sampling for people with elevated levels of the multi-biomarker score was over four times higher than for long-term risk (8.0 [4.1–15.6]). If these hypothesis generating findings on increased susceptibility to severe pneumonia during the first few years after blood sampling extend to severe COVID-19, metabolic biomarker profiling could potentially complement existing tools for identifying individuals at high risk. These results provide novel molecular understanding on how metabolic biomarkers reflect the susceptibility to severe COVID-19 and other infections in the general population.


2019 ◽  
Vol 65 (2) ◽  
pp. 321-332 ◽  
Author(s):  
Signe E J Hansen ◽  
Christian M Madsen ◽  
Anette Varbo ◽  
Børge G Nordestgaard

Abstract BACKGROUND How mild-to-moderate hypertriglyceridemia (2–10 mmol/L; 177–886 mg/dL) potentially causes acute pancreatitis is unknown; however, cellular studies indicate that inflammation might be a driver of disease progression. We tested the hypotheses that (a) mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and that (b) the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis depends on low-grade inflammation. METHODS From the Copenhagen General Population Study and the Copenhagen City Heart Study, 117865 men and women 20–100+ years of age with measurements of nonfasting plasma triglycerides at baseline were followed prospectively for development of acute pancreatitis. RESULTS After multivariable adjustment, a 1 mmol/L (89 mg/dL) higher nonfasting triglyceride concentration was associated with 17% (95% CI, 16%–18%, P = 3 × 10−17) higher plasma C-reactive protein (CRP) and a 4.2% (4.0%–4.4%, P = 6 × 10−17) higher blood leukocyte count. Higher concentrations of nonfasting triglycerides were associated almost linearly with higher risk of acute pancreatitis (P for trend = 5 × 10−6), with hazard ratios of 1.5 (95% CI, 0.9–2.5), 2.0 (95% CI, 1.1–3.6), 2.2 (95% CI, 1.0–4.7), 4.2 (95% CI, 1.6–11.5), and 7.7 (95% CI, 3.0–19.8) in individuals with nonfasting triglycerides of 1.00–1.99 mmol/L (89–176 mg/dL; 46% of the population), 2.00–2.99 mmol/L (177–265 mg/dL; 17%), 3.00–3.99 mmol/L (266–353 mg/dL; 6%), 4.00–4.99 mmol/L (354–442 mg/dL; 2%), and ≥5mmol/L(443 mg/dL; 2%), respectively, vs individuals with <1 mmol/L (89 mg/dL; 27%). The association with risk of acute pancreatitis appeared more pronounced in individuals with CRP of ≥1.39 mg/L (P for trend = 0.001) and leukocytes of ≥7 × 109/L (P = 2 × 10−4) than in those with CRP <1.39 mg/L (P = 0.03) and leukocytes <7 × 109/L (P = 0.04); however, there was no formal evidence of statistical interaction (P = 0.38 for CRP and P = 0.41 for leukocytes). CONCLUSIONS Mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and higher risk of acute pancreatitis. The association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis is possibly partly mediated by low-grade inflammation.


2020 ◽  
Vol 41 (24) ◽  
pp. 2288-2299 ◽  
Author(s):  
Morten Kaltoft ◽  
Anne Langsted ◽  
Børge G Nordestgaard

Abstract Aims We tested the hypothesis that higher levels of plasma triglycerides and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis. Methods and results We included 108 559 individuals from the Copenhagen General Population Study. Plasma triglycerides, remnant cholesterol (total cholesterol minus low-density lipoprotein and high-density lipoprotein cholesterol), and 16 genetic variants causing such increased or decreased levels were determined. Incident aortic valve stenosis occurred in 1593 individuals. Observationally compared to individuals with triglycerides <1 mmol/L (<89 mg/dL), the multifactorially adjusted hazard ratio for aortic valve stenosis was 1.02 [95% confidence interval (CI) 0.87–1.19] for individuals with triglycerides of 1.0–1.9 mmol/L (89–176 mg/dL), 1.22 (1.02–1.46) for 2.0–2.9 mmol/L (177–265 mg/dL), 1.40 (1.11–1.77) for 3.0–3.9 mmol/L (266–353 mg/dL), 1.29 (0.88–1.90) for 4.0–4.9 mmol/L (354–442 mg/dL), and 1.52 (1.02–2.27) for individuals with triglycerides ≥5 mmol/L (≥443 mg/dL). By age 85, the cumulative incidence of aortic valve stenosis was 5.1% for individuals with plasma triglycerides <2.0 mmol/L (77 mg/dL), 6.5% at 2.0–4.9 mmol/L (177–442 mg/dL), and 8.2% for individuals with plasma triglycerides ≥5.0 mmol/L (443 mg/dL). The corresponding values for remnant cholesterol categories were 4.8% for <0.5 mmol/L (19 mg/dL), 5.6% for 0.5–1.4 mmol/L (19–57 mg/dL), and 7.4% for ≥1.5 mmol/L (58 mg/dL). Genetically, compared to individuals with allele score 13–16, odds ratios for aortic valve stenosis were 1.30 (95% CI 1.20–1.42; Δtriglycerides +12%; Δremnant cholesterol +11%) for allele score 17–18, 1.41 (1.31–1.52; +25%; +22%) for allele score 19–20, and 1.51 (1.22–1.86; +51%; +44%) for individuals with allele score 21–23. Conclusion Higher triglycerides and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.


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