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Assessing cardiovascular disease: looking beyond cholesterol
1Mid-Cheshire Hospitals NHS Foundation Trust. Leighton Hospital, Crewe, Cheshire, UK.
Insights
Low-density lipoprotein (LDL)-cholesterol is a poor predictor of cardiovascular disease (CVD). A thrombogenic model, focusing on endothelial damage and thrombus formation, offers a more accurate explanation for CVD development and progression.
Area of Science:
- Cardiovascular Science
- Thrombosis Research
- Endothelial Biology
Background:
- Low-density lipoprotein (LDL)-cholesterol is a weak predictor of cardiovascular disease (CVD), explaining only a small proportion of overall risk.
- Current risk calculators like ASCVD and Qrisk3 do not use LDL-cholesterol levels.
- Recent studies suggest modest benefits of statins, not strongly mediated by LDL reduction.
Purpose of the Study:
- To challenge the traditional cholesterol hypothesis of atherosclerosis.
- To propose an alternative 'thrombogenic' hypothesis for atherosclerotic cardiovascular disease (ASCVD).
- To highlight the role of endothelial damage and thrombus formation in ASCVD.
Main Methods:
- Review of existing literature on cardiovascular disease etiology.
- Analysis of the limitations of the cholesterol hypothesis.
- Examination of the impact of endothelial damage on cardiovascular health.
Main Results:
- The cholesterol hypothesis inadequately explains individual and population-level cardiovascular risk.
- Endothelial damage, as seen during the SARS-CoV2 pandemic, can trigger thrombus formation.
- Endothelial damage and subsequent thrombus formation are proposed as a primary mechanism for acute cardiovascular events and ASCVD progression.
Conclusions:
- The 'thrombogenic' hypothesis provides a more valid causal model for ASCVD than the cholesterol hypothesis.
- Focusing beyond cholesterol to endothelial damage and thrombosis may offer better insights into cardiovascular risk.
- Understanding the thrombogenic pathway is crucial for developing new strategies for ASCVD prevention and treatment.
Purpose Of Review:
The low-density lipoprotein (LDL)-cholesterol level is a weak predictor of developing cardiovascular (CV) disease and can only explain a small proportion of CV risk. It is not used to determine CV risk on either the atherosclerotic cardiovascular disease (ASCVD) calculator in the United States, or the Qrisk3 in the UK.A study in JAMA in 2022 suggested that ' the absolute benefits of statins are modest and may not be strongly mediated through the degree of LDL reduction '. Perhaps it is time to look beyond cholesterol to a different causal model - the 'thrombogenic' model of ASCVD.
Recent Findings:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic demonstrated that infectious agents damage the endothelium and the glycocalyx - the glycoprotein layer protecting underlying endothelial cells. There are numerous other conditions leading to this kind of damage, which can trigger thrombus formation, causing strokes and myocardial infarctions.Although these are acute events, they highlight a mechanism for the development of ASCVD which centres on endothelial damage and thrombus formation as both the primary causal mechanism for acute events, and the driver behind progression towards atherosclerotic plaque development.
Summary:
The cholesterol hypothesis, that a raised LDL is directly causal for ASCVD, does not adequately explain cardiovascular risk in individuals, or populations. An alternative 'thrombogenic' hypothesis is proposed as a more valid causal model.
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