Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly supports that elevated lipoprotein (a) Lp(a) is a causal risk factor for ...cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis. The Mendelian randomization approach used to infer causality is generally not affected by confounding and reverse causation, the major problems of observational epidemiology. This approach is particularly valuable to study causality of Lp(a), as single genetic variants exist that explain 27–28% of all variation in plasma Lp(a). The most important genetic variant likely is the kringle IV type 2 (KIV-2) copy number variant, as the apo(a) product of this variant influences fibrinolysis and thereby thrombosis, as opposed to the Lp(a) particle per se. We speculate that the physiological role of KIV-2 in Lp(a) could be through wound healing during childbirth, infections, and injury, a role that, in addition, could lead to more blood clots promoting stenosis of arteries and the aortic valve, and myocardial infarction. Randomized placebo-controlled trials of Lp(a) reduction in individuals with very high concentrations to reduce cardiovascular disease are awaited. Recent genetic evidence documents elevated Lp(a) as a cause of myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis.
Abstract
Aims
Several lipoprotein(a)-lowering therapies are currently being developed with the long-term goal of reducing cardiovascular disease and mortality; however, the relationship between ...lipoprotein(a) and mortality is unclear. We tested the hypothesis that lipoprotein(a) levels are associated with risk of mortality.
Methods and results
We studied individuals from two prospective studies of the Danish general population, of which 69 764 had information on lipoprotein(a) concentrations, 98 810 on LPA kringle-IV type 2 (KIV-2) number of repeats, and 119 094 on LPA rs10455872 genotype. Observationally, lipoprotein(a) >93 mg/dL (199 nmol/L; 96th–100th percentiles) vs. <10 mg/dL (18 nmol/L; 1st–50th percentiles) were associated with a hazard ratio of 1.50 (95% confidence interval 1.28–1.76) for cardiovascular mortality and of 1.20 (1.10–1.30) for all-cause mortality. The median survival for individuals with lipoprotein(a) >93 mg/dL (199 nmol/L; 96th–100th percentiles) and ≤93 mg/dL (199 nmol/L; 1st–95th percentiles) were 83.9 and 85.1 years (log rank P = 0.005). For cardiovascular mortality, a 50 mg/dL (105 nmol/L) increase in lipoprotein(a) levels was associated observationally with a hazard ratio of 1.16 (1.09–1.23), and genetically with risk ratios of 1.23 (1.08–1.41) based on LPA KIV2 and of 0.98 (0.88–1.09) based on LPA rs10455872. For all-cause mortality, corresponding values were 1.05 (1.01–1.09), 1.10 (1.04–1.18), and 0.97 (0.92–1.02), respectively. Finally, for a similar cholesterol content increase, lipoprotein(a) was more strongly associated with cardiovascular and all-cause mortality than low-density lipoprotein, implying that the mortality effect of high lipoprotein(a) is above that explained by its cholesterol content.
Conclusion
High levels of lipoprotein(a), through corresponding low LPA KIV-2 number of repeats rather than through high cholesterol content were associated with high risk of mortality. These findings are novel.
In cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non–high-density lipoprotein (non-HDL) cholesterol are secondary ...targets.
This study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction.
In total, 13,015 statin-treated patients from the Copenhagen General Population Study were included with 8 years median follow-up. Cox regressions among apoB, non-HDL cholesterol, and LDL cholesterol, respectively, and all-cause mortality or myocardial infarction were examined on continuous scales by restricted cubic splines and by categories of concordant and discordant values defined by medians.
High apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, whereas no such associations were found for high LDL cholesterol. Compared with concordant values below medians, discordant apoB above the median with LDL cholesterol below yielded hazard ratios of 1.21 (95% confidence interval CI: 1.07 to 1.36) for all-cause mortality and 1.49 (95% CI: 1.15 to 1.92) for myocardial infarction. Corresponding values for high non-HDL cholesterol with low LDL cholesterol were 1.18 (95% CI: 1.02 to 1.36) and 1.78 (95% CI: 1.35 to 2.34). In contrast, discordant high LDL cholesterol with low apoB or non-HDL cholesterol was not associated with increased risk of all-cause mortality or myocardial infarction. Also, discordant high apoB with low non-HDL cholesterol yielded hazard ratios of 1.21 (95% CI: 1.03 to 1.41) for all-cause mortality and of 0.93 (95% CI: 0.62 to 1.40) for myocardial infarction. Furthermore, dual discordant apoB and non-HDL cholesterol above the medians with LDL cholesterol below presented hazard ratios of 1.23 (95% CI: 1.07 to 1.43) for all-cause mortality and 1.82 (95% CI: 1.37 to 2.42) for myocardial infarction.
In statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL cholesterol or non-HDL cholesterol, and apoB in addition is a more accurate marker of risk of myocardial infarction than LDL cholesterol.
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Severe hypertriglyceridemia is associated with increased risk of acute pancreatitis. However, the threshold above which triglycerides are associated with acute pancreatitis is unclear.
To test the ...hypothesis that nonfasting mild-to-moderate hypertriglyceridemia (177-885 mg/dL; 2-10 mmol/L) is also associated with acute pancreatitis.
This prospective cohort study examines individuals from the Copenhagen General Population Study in 2003 to 2015 and the Copenhagen City Heart Study initiated in 1976 to 1978 with follow-up examinations in 1981 to1983, 1991 to 1994, and in 2001 to 2003. Median follow-up was 6.7 years (interquartile range, 4.0-9.4 years); and includes 116 550 individuals with a triglyceride measurement from the Copenhagen General Population Study (n = 98 649) and the Copenhagen City Heart Study (n = 17 901). All individuals were followed until the occurrence of an event, death, emigration, or end of follow-up (November 2014), whichever came first.
Plasma levels of nonfasting triglycerides.
Hazard ratios (HRs) for acute pancreatitis (n = 434) and myocardial infarction (n = 3942).
Overall, 116 550 individuals were included in this study (median interquartile range age, 57 47-66 years). Compared with individuals with plasma triglyceride levels less than 89 mg/dL (<1 mmol/L), the multivariable adjusted HRs for acute pancreatitis were 1.6 (95% CI, 1.0-2.6; 4.3 events/10 000 person-years) for individuals with triglyceride levels of 89 mg/dL to 176 mg/dL (1.00 mmol/L-1.99 mmol/L), 2.3 (95% CI, 1.3-4.0; 5.5 events/10 000 person-years) for 177 mg/dL to 265 mg/dL (2.00 mmol/L-2.99 mmol/L), 2.9 (95% CI, 1.4-5.9; 6.3 events/10 000 person-years) for 366 mg/dL to 353 mg/dL (3.00 mmol/L-3.99 mmol/L), 3.9 (95% CI, 1.5-10.0; 7.5 events/10 000 person-years) for 354 mg/dL-442 mg/dL (4.00 mmol/L-4.99 mmol/L), and 8.7 (95% CI, 3.7-20.0; 12 events/10 000 person-years) for individuals with triglyceride levels greater than or equal to 443 mg/dL (≥5.00 mmol/L) (trend, P = 6 × 10-8). Corresponding HRs for myocardial infarction were 1.6 (95% CI, 1.4-1.9; 41 events/10 000 person-years), 2.2 (95% CI, 1.9-2.7; 57 events/10 000 person-years), 3.2 (95% CI, 2.6-4.1; 72 events/10 000 person-years), 2.8 (95% CI, 2.0-3.9; 68 events/10 000 person-years), and 3.4 (95% CI, 2.4-4.7; 78 events/10 000 person-years) (trend, P = 6 × 10-31), respectively. The multivariable adjusted HR for acute pancreatitis was 1.17 (95% CI, 1.10-1.24) per 89 mg/dL (1 mmol/L) higher triglycerides. When stratified by sex, age, education, smoking, hypertension, statin use, study cohort, diabetes, body mass index (calculated as weight in kilograms divided by height in meters squared), alcohol intake, and gallstone disease, these results were similar with no statistical evidence of interaction.
Nonfasting mild-to-moderate hypertriglyceridemia from 177 mg/dL (2 mmol/L) and above is associated with high risk of acute pancreatitis, with HR estimates higher than for myocardial infarction.
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.
Prospective cohort study.
Denmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years.
Individuals randomly selected from the national Danish Civil Registration System.
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).
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.
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).
The reason why lipoprotein(a) concentrations are raised in individuals with clinical familial hypercholesterolaemia is unclear. We tested the hypotheses that high lipoprotein(a) cholesterol and LPA ...risk genotypes are a possible cause of clinical familial hypercholesterolaemia, and that individuals with both high lipoprotein(a) concentrations and clinical familial hypercholesterolaemia have the highest risk of myocardial infarction.
We did a prospective cohort study that included data from 46 200 individuals from the Copenhagen General Population Study who had lipoprotein(a) measurements and were genotyped for common familial hypercholesterolaemia mutations. Individuals receiving cholesterol-lowering drugs had their concentrations of LDL and total cholesterol multiplied by 1·43, corresponding to an estimated 30% reduction in LDL cholesterol from the treatment. In lipoprotein(a) cholesterol-adjusted analyses, total cholesterol and LDL cholesterol were adjusted for the lipoprotein(a) cholesterol content by subtracting 30% of the individuals' lipoprotein(a) total mass before total and LDL cholesterol were used for diagnosis of clinical familial hypercholesterolaemia. We used modified Dutch Lipid Clinic Network (DLCN), Simon Broome, and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria to clinically diagnose familial hypercholesterolaemia. Cox proportional hazard regression calculated hazard ratios (95% CI) of myocardial infarction.
Using unadjusted LDL cholesterol, mean lipoprotein(a) concentrations were 23 mg/dL in individuals unlikely to have familial hypercholesterolaemia, 32 mg/dL in those with possible familial hypercholesterolaemia, and 35 mg/dL in those with probable or definite familial hypercholesterolaemia (ptrend<0·0001). However, when adjusting LDL cholesterol for lipoprotein(a) cholesterol content the corresponding values were 24 mg/dL for individuals unlikely to have familial hypercholesterolaemia, 22 mg/dL for those with possible familial hypercholesterolaemia, and 21 mg/dL for those with probable or definite familial hypercholesterolaemia (ptrend=0·46). High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia and LPA risk genotypes were more frequent in clinical familial hypercholesterolaemia, whereas lipoprotein(a) concentrations were similar in those with and without familial hypercholesterolaemia mutations. The hazard ratios (HRs) for myocardial infarction compared with individuals unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less were 1·4 (95% CI 1·1-1·7) in those unlikely to have familial hypercholesterolaemia and lipoprotein(a) concentrations of more than 50 mg/dL, 3·2 (2·5-4·1) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of 50 mg/dL or less, and 5·3 (3·6-7·6) in those with possible, probable, or definite familial hypercholesterolaemia and lipoprotein(a) concentration of more than 50 mg/dL. In analyses using Simon Broome or MEDPED criteria, results were similar to those using DLCN criteria to diagnose clinical familial hypercholesterolaemia.
High lipoprotein(a) concentrations and corresponding LPA risk genotypes represent novel risk factors for clinical familial hypercholesterolaemia. Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction.
Danish Heart Association and IMK General Fund, Denmark.
One fifth of the world population live in East Asia comprising Japan, Korea, and China where ischemic heart disease, a major component of atherosclerotic cardiovascular disease (ASCVD), is the second ...most frequent cause of death. Each of low-density lipoproteins (LDL), remnant lipoproteins, and lipoprotein(a), summarized as non-high-density lipoproteins (non-HDL) or apolipoprotein B (apoB) containing lipoproteins, causes ASCVD. However, a significant proportion of the evidence on lipoproteins and lipoprotein cholesterol with risk of ASCVD came from White people mainly living in Europe and North America and not from people living in East Asia or of East Asian descent. With a unique biological, geohistorical, and social background in this world region, East Asians have distinctive characteristics that might have potential impact on the association of lipoproteins and lipoprotein cholesterol with risk of ASCVD. Considering the movement across national borders in the World, understanding of lipoprotein and lipoprotein cholesterol evidence on ASCVD in East Asia is important for both East Asian and non-East Asian populations wherever they live in the World.In this review, we introduce the biological features of lipoproteins and lipoprotein cholesterol and the evidence for their association with risk of ASCVD in East Asian and European populations. We also provide an overview of guideline recommendations for prevention of ASCVD in these two different world regions. Finally, specific preventive strategies and future perspectives are touched upon.
The European Atherosclerosis Society-European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein ...quantification for cardiovascular risk management.
We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. (
) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations <70 mg/dL (1.8 mmol/L). Increased lipoprotein(a) should be excluded in patients not achieving LDL cholesterol goals with treatment. Non-HDL cholesterol includes the atherogenic risk component of remnant cholesterol and can be calculated in a standard nonfasting lipid panel without additional expense. ApoB more accurately reflects LDL particle number. (
) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. (
) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle-targeted treatment reduces the number of cardiovascular events and healthcare-related costs than treatment targeted to LDL cholesterol.
Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels.
Increased concentrations of calculated remnant cholesterol in triglyceride-rich lipoproteins are observationally and genetically, causally associated with increased risk of ischemic heart disease; ...however, when measured directly, the fraction of plasma cholesterol present in remnant particles is unclear. We tested the hypothesis that a major fraction of plasma cholesterol is present in remnant lipoproteins in individuals in the general population.
We examined 9293 individuals from the Copenhagen General Population Study using nuclear magnetic resonance spectroscopy measurements of total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration. Fourteen subclasses of decreasing size and their lipid constituents were analysed: six subclasses were very low-density lipoprotein (VLDL), one intermediate-density lipoprotein (IDL), three low-density lipoprotein (LDL), and four subclasses were high-density lipoprotein (HDL). Remnant lipoproteins were VLDL and IDL combined.
Mean nonfasting cholesterol concentration was 1.84 mmol/L (72 mg/dL) for remnants, 2.01 mmol/L (78 mg/dL) for LDL, and 1.83 mmol/L (71 mg/dL) for HDL, equivalent to remnants containing 32% of plasma total cholesterol. Of 14 lipoprotein subclasses, large LDL and IDL were the ones containing most of plasma cholesterol. The plasma concentration of remnant cholesterol was from ∼1.4 mmol/L (54 mg/dL) at age 20 to ∼1.9 mmol/L (74 mg/dL) at age 60. Corresponding values for LDL cholesterol were from ∼1.5 mmol/L (58 mg/dL) to ∼2.1 mmol/L (81 mg/dL).
Using direct measurements, one third of total cholesterol in plasma was present in remnant lipoproteins, that is, in the triglyceride-rich lipoproteins IDL and VLDL.
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•Using NMR, a third of plasma cholesterol was present in remnant lipoproteins.•Of 14 lipoprotein subclasses, large LDL and IDL were containing most cholesterol.•Directly measured remnant cholesterol was highest in older individuals.
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