In a recent review published in the journal Nature Reviews Cardiology, a group of authors reviewed the Low-Density Lipoprotein (LDL) (a type of cholesterol that can build up in artery walls) cumulative exposure hypothesis and its implications for atherosclerotic cardiovascular disease (ASCVD) (a condition caused by the buildup of plaques in the arteries) prevention.
Review Article: The LDL cumulative exposure hypothesis: evidence and practical applications. Image Credit: Explode / Shutterstock
Background
ASCVD is the leading cause of morbidity and mortality worldwide. It is caused by the progressive trapping of cholesterol-carrying LDL and other apolipoprotein B(APOB)-containing lipoproteins within the arterial wall. Over time, as more LDL particles become trapped, atherosclerotic plaques grow, increasing the risk of ASCVD events. The effect of LDL on ASCVD depends on both the magnitude and duration of exposure. Maintaining low LDL-cholesterol (LDL-C) levels over time can reduce atherogenic lipoproteins (Lipoproteins, including LDL, that promote the formation of fatty deposits in the arteries) in the artery wall, slow atherosclerosis ( the process of plaque buildup in the arteries, causing them to harden and narrow) progression, and lower the lifetime risk of ASCVD events. Further research is needed to refine the cumulative exposure hypothesis and develop personalized strategies for effectively lowering LDL-C levels to prevent ASCVD. The review highlights the need for further research to refine the cumulative exposure hypothesis and develop personalized strategies for effectively lowering LDL-C levels to prevent ASCVD.
The LDL cumulative exposure hypothesis
The cumulative exposure hypothesis posits that both the size of the accumulated plaque burden and the corresponding absolute risk of cardiovascular events are determined by the cumulative exposure to LDL. This hypothesis is supported by the observation that individuals with higher lifelong LDL exposure levels have larger plaque burdens and higher risks of cardiovascular events.
Evidence supporting the hypothesis
Several lines of evidence support the cumulative exposure hypothesis. Experimental studies demonstrate that the number of LDL particles crossing the endothelial barrier is proportional to plasma LDL-C levels. Autopsy studies have demonstrated early atherosclerotic lesions in teenagers and young adults, suggesting that LDL trapping begins early in life. Non-invasive imaging studies reveal that detectable atherosclerotic plaques increase with age, further supporting the idea that cumulative LDL exposure drives plaque growth.
LDL cumulative exposure hypothesis: practical applications
Rationale and methodology
Plasma LDL-C levels follow a characteristic trajectory over a lifetime, rising steadily in men until about age 55 and in women until age 65, after which they gradually decline. Summing LDL-C measurements over time to calculate cumulative exposure provides a biomarker capturing both the magnitude and duration of exposure, which helps estimate accumulated plaque burden and assess ASCVD risk.
Estimating risk
The cumulative LDL threshold at which ASCVD events occur can be plotted against cardiovascular event rates. For men with average LDL-C levels, ASCVD risk reaches 1% after 130 plaque-years and 10% after 200 plaque-years. For women, these thresholds are higher. The review provides detailed graphs and data showing these thresholds, illustrating the importance of lifelong LDL-C management. Individuals with higher-than-average LDL-C levels experience faster plaque progression and earlier cardiovascular events, while those with lower levels have delayed events and reduced risk.
Other causes of artery wall injury
Factors like elevated systolic blood pressure (SBP) and diabetes can lower the threshold for cumulative LDL exposure at which cardiovascular events occur. Elevated SBP and diabetes increase LDL trapping and adverse coronary artery remodeling, respectively, leading to higher cardiovascular event rates at lower cumulative LDL exposures.
Relationship between cumulative LDL exposure and coronary artery calcium (CAC)
Cumulative LDL exposure estimates plaque burden and ASCVD risk. CAC measurement provides an alternative method, with CAC scores becoming non-zero after 150 plaque-years of LDL exposure in men, indicating late-stage atherosclerosis. Effective LDL-C lowering must begin before CAC scores rise.
Estimating benefits
Sustained LDL-C reduction can substantially lower ASCVD risk. Studies on genetic variants and public health campaigns, like Finland's, support early, sustained LDL-C reduction. The Tsimané people's low LDL-C levels and low ASCVD risk further demonstrate these benefits. The review also discusses novel financial instruments using private capital to fund prevention programs by quantifying LDL's causal effect, aligning incentives to reduce cumulative LDL exposure and prevent cardiovascular events. Personalized prevention strategies, aided by deep learning algorithms, can optimize LDL-C lowering.
Informing clinical practice guidelines
Guidelines increasingly endorse reducing cumulative LDL exposure to prevent ASCVD, advocating early, sustained LDL-C reduction. This preventive approach is vital for low- and middle-income countries, shifting focus from treating disease to preventing it.
Funding cardiovascular prevention
Novel financial instruments using private capital can fund prevention programs by quantifying LDL's causal effect, aligning incentives to reduce cumulative LDL exposure and prevent cardiovascular events.
Future Directions
Deep learning and machine learning
Recent advances in deep learning and machine learning offer promising tools for predicting the benefits of lowering LDL-C at various life stages. These algorithms can model the biological causal effects of LDL exposure, helping estimate interventions' optimal timing and intensity.
Long-term LDL-C lowering
Evidence from Mendelian randomization studies and real-world observations suggests that modest LDL-C lowering started earlier in life is more effective in reducing lifetime ASCVD risk compared to aggressive lowering later in life. This finding emphasizes the importance of early intervention to achieve long-term benefits.
Conclusions
To summarize, ASCVD is caused by the progressive trapping of cholesterol-containing LDL particles within the artery wall. Summing LDL-C levels over time to calculate cumulative exposure to LDL creates a biomarker for estimating the size of the accumulated plaque burden, tracking plaque progression, and estimating the risk of acute ASCVD events. Reducing cumulative LDL exposure lowers the lifetime risk of ASCVD by slowing atherosclerosis progression. The clinical benefit of LDL lowering depends on its magnitude, duration, and timing. The review suggests that novel injectable therapies and advanced Artificial Intelligence (AI) algorithms can personalize and optimize LDL-C reduction strategies, enhancing ASCVD prevention and enabling innovative trial designs and funding mechanisms.