Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial
Uffe Ravnskov1, Michel de Lorgeril2, Malcolm Kendrick3
1Magle Stora Kyrkogata 9, 22350 Lund, Sweden.
Insights
Familial hypercholesterolemia (FH) may not be solely caused by high LDL-C. Research suggests other factors like coagulation may be more critical for cardiovascular disease (CVD) in FH patients.
Area of Science:
- Cardiology
- Genetics
- Biochemistry
Background:
- Familial hypercholesterolemia (FH) is widely attributed to high low-density-lipoprotein cholesterol (LDL-C) as the primary cause of cardiovascular disease (CVD).
- However, existing evidence presents inconsistencies with established causality criteria, questioning the sole role of LDL-C.
Purpose of the Study:
- To critically evaluate the established causal link between high LDL-C and CVD in FH.
- To explore alternative or co-existing risk factors for CVD in individuals with FH.
Main Methods:
- Review of existing literature and observational data concerning FH, LDL-C levels, atherosclerosis progression, and CVD incidence.
- Analysis of findings from controlled, randomized cholesterol-lowering trials involving FH individuals.
- Examination of studies investigating coagulation factors and other genetic predispositions in FH kindreds.
Main Results:
- Atherosclerosis severity does not consistently correlate with LDL-C levels in FH patients.
- FH individuals with and without CVD exhibit similar high LDL-C levels.
- Randomized trials show questionable or no significant benefit from cholesterol-lowering interventions in FH.
- Studies indicate that coagulation factors may play a significant role in CVD development within FH populations.
Conclusions:
- The causal role of high LDL-C in FH-related CVD is questionable, suggesting other inherited risk factors are likely involved.
- Systematic investigation into diverse risk factors, including coagulation, is urgently needed for FH.
- Current statin treatments for FH lack proven benefit and carry risks; anticoagulative therapies targeting elevated coagulation factors may offer a more effective alternative.
Abstract:
High low-density-lipoprotein cholesterol (LDL-C) is routinely described as the main cause of cardiovascular disease (CVD) in familial hypercholesterolemia (FH). However, numerous observations are in conflict with Bradford Hill's criteria for causality: a) degree of atherosclerosis is not associated with LDL-C; b) on average the life span of people with FH is about the same as for other people; c) LDL-C of people with FH without CVD is almost as high as in FH patients of the same age with CVD; and d) questionable benefit or none at all have been achieved in the controlled, randomized cholesterol-lowering trials that have included FH individuals only. Obviously, those individuals with FH who suffer from CVD may have inherited other and more important risk factors of CVD than high LDL-C. In accordance, several studies of FH individuals have shown that various coagulation factors may cause CVD. Equally, some non-FH members of an FH kindred with early CVD, have been found to suffer from early CVD as well. Cholesterol-lowering has only been successful in an animal experiment by using probucol, which has anticoagulant effects as well. We conclude that systematic studies of all kinds of risk factors among FH individuals are urgently required, because today millions of people with FH are treated with statins, the benefit of which in FH is unproven, and which have many serious side effects. We predict that treatment of FH individuals with elevated coagulation factors with anticoagulative drugs is more effective than statin treatment alone.
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