Hdl cholesterol too high
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Some studies suggest extremely high HDL-C levels are associated with increased risks of cardiovascular disease and all-cause mortality, while other studies highlight the protective role of HDL cholesterol efflux capacity and its potential benefits for reducing cardiovascular risk.
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The Impact of Extremely High HDL Cholesterol on Cardiovascular Health
Introduction to HDL Cholesterol and Cardiovascular Risk
High-density lipoprotein cholesterol (HDL-C) is often referred to as "good cholesterol" due to its role in transporting cholesterol from peripheral tissues back to the liver, which helps prevent atherosclerosis and other cardiovascular diseases (CVD). However, recent studies have challenged the notion that higher HDL-C levels are always beneficial, suggesting that extremely high levels of HDL-C may actually increase cardiovascular risk .
Extremely High HDL-C and Cardiovascular Mortality
Increased Risk of Atherosclerotic CVD
A pooled analysis of nine Japanese cohort studies involving 43,407 participants found that extremely high levels of HDL-C (≥90 mg/dL) were significantly associated with an increased risk of atherosclerotic CVD mortality. The study reported a hazard ratio of 2.37 for total atherosclerotic CVD mortality, indicating a more than twofold increase in risk compared to individuals with HDL-C levels between 40-59 mg/dL. This risk was particularly pronounced among current drinkers.
U-Shaped Mortality Risk
Research from the Copenhagen City Heart Study and the Copenhagen General Population Study, which included over 117,000 participants, revealed a U-shaped association between HDL-C levels and all-cause mortality. Both extremely high and low HDL-C concentrations were linked to higher mortality rates. For men, the lowest mortality risk was observed at HDL-C levels of 73 mg/dL, while for women, it was at 93 mg/dL. Hazard ratios for all-cause mortality were significantly higher for individuals with HDL-C levels above these thresholds.
HDL Functionality vs. HDL-C Levels
Importance of HDL Functionality
Recent evidence suggests that the functionality of HDL particles, rather than their concentration, plays a crucial role in cardiovascular protection. HDL cholesterol efflux capacity (CEC), which measures the ability of HDL to remove cholesterol from macrophages, is a key indicator of HDL functionality. Studies have shown that higher CEC is strongly inversely associated with carotid intima-media thickness and the likelihood of coronary artery disease, independent of HDL-C levels.
Genetic and Clinical Insights
Genetic studies and clinical trials have further complicated the understanding of HDL-C's role in cardiovascular health. Some genetic disorders characterized by extremely high HDL-C levels do not confer reduced cardiovascular risk, highlighting the importance of HDL functionality over mere concentration. Additionally, pharmacological attempts to raise HDL-C levels have not consistently resulted in reduced cardiovascular events, suggesting that simply increasing HDL-C is not a viable therapeutic strategy.
Gender and Population Differences
Gender-Specific Findings
Subgroup analyses have indicated that the relationship between extremely high HDL-C and cardiovascular risk may differ by gender. For instance, extremely high HDL-C levels were associated with a reduced risk of CVD mortality in women but not in men, and a lower risk of stroke in men but not in women. This suggests that gender-specific factors may influence the impact of HDL-C on cardiovascular health.
Population-Specific Insights
The adverse effects of extremely high HDL-C levels have been observed across different populations. For example, a study involving hypertensive patients in Southern Italy found a U-shaped association between HDL-C levels and cardiovascular events, with both low and high HDL-C levels linked to increased risk. Interestingly, this increased risk was not observed in female patients.
Conclusion
While HDL-C has long been considered protective against cardiovascular disease, emerging evidence suggests that extremely high levels of HDL-C may paradoxically increase cardiovascular risk. The functionality of HDL particles appears to be more important than their concentration in mediating cardiovascular protection. These findings underscore the need for a nuanced understanding of HDL-C's role in cardiovascular health and caution against assuming that higher HDL-C levels are always beneficial. Further research is needed to confirm these findings and to explore the mechanisms underlying the adverse effects of extremely high HDL-C levels.
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