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Lipoprotein(a): is it more, less or equal to LDL as a causal factor for cardiovascular disease and mortality?
Anne Langsted1,2,3, Børge G Nordestgaard1,2,3
1Department of Clinical Biochemistry.
Insights
Low-density lipoprotein (LDL) and lipoprotein(a) show similar causal risks for heart attack. However, lipoprotein(a) is a more significant factor for cardiovascular and all-cause mortality, potentially due to its structure.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Cardiovascular disease (CVD) remains a leading cause of mortality worldwide.
- Lipid profiles, including low-density lipoprotein (LDL) cholesterol and lipoprotein(a) [Lp(a)], are critical in assessing CVD risk.
- Understanding the distinct causal roles of LDL and Lp(a) is essential for targeted prevention strategies.
Purpose of the Study:
- To directly compare the causal roles of LDL cholesterol and Lp(a) in cardiovascular disease and mortality.
- To review recent scientific literature on the comparative impact of LDL and Lp(a) on health outcomes.
Main Methods:
- Observational analyses of approximately 100,000 individuals from the Copenhagen General Population Study.
- Genetic analyses to determine causal risk ratios for myocardial infarction and mortality.
- Assessment of hazard ratios for myocardial infarction, cardiovascular mortality, and all-cause mortality per unit increase in LDL and Lp(a) cholesterol.
Main Results:
- On a cholesterol basis, LDL and Lp(a) demonstrated similar causal risk for myocardial infarction (HR 1.3 for LDL, 1.6 for Lp(a)).
- Genetic analyses indicated comparable causal risk ratios for myocardial infarction (2.1 for LDL, 2.0 for Lp(a)).
- Lp(a) showed a greater association with mortality risk compared to LDL (HR 1.18 vs. 1.05 for cardiovascular mortality, 1.07 vs. 1.01 for all-cause mortality per 15 mg/dl increase).
Conclusions:
- Lipoprotein(a) is a significant causal factor for cardiovascular mortality, potentially exceeding the impact of LDL cholesterol.
- The structural characteristics of Lp(a), particularly its resemblance to plasminogen via apolipoprotein(a) kringle IV-2, may contribute to its pathogenicity beyond its cholesterol content.
- Further research into Lp(a) structure and function is warranted for novel therapeutic targets.
Purpose Of Review:
To summarize the recent studies directly comparing LDL and lipoprotein(a) as causal factors for cardiovascular disease and mortality.
Recent Findings:
In approximately 100,000 individuals from the Copenhagen General Population Study for risk of myocardial infarction, in observational analyses per 39 mg/dl (1 mmol/l) cholesterol increase, the hazard ratio was 1.3 (95% confidence interval: 1.2-1.3) for LDL cholesterol and 1.6 (1.4-1.9) for lipoprotein(a) cholesterol. In corresponding genetic analyses, the causal risk ratio was 2.1 (1.3-3.4) for LDL and 2.0 (1.6-2.6) for lipoprotein(a). Also, a 15 mg/dl (0.39 mmol/l) cholesterol increase was associated with a hazard ratio for cardiovascular mortality of 1.05 (1.04-1.07) for LDL cholesterol and 1.18 (1.12-1.25) for lipoprotein(a) cholesterol. Corresponding values for all-cause mortality were 1.01 (1.00-1.01) for LDL cholesterol and 1.07 (1.04-1.10) for lipoprotein(a) cholesterol. In genetic, causal analyses, the mortality increases for elevated lipoprotein(a) appeared to be through apolipoprotein(a) kringle IV-2 rather than through lipoprotein(a) levels per se.
Summary:
On cholesterol scales, lipoprotein(a) and LDL appeared equal as causal factors for myocardial infarction; however, lipoprotein(a) was most important for mortality. Lipoprotein(a) effects may not only be due to cholesterol content but could also be due to the structure of lipoprotein(a) resembling plasminogen.
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