The atherogenic lipoprotein subfraction studies in patients with familial hypercholesterolaemia
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Date
2014-03-25
Authors
Raao, Frederick Johan
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Abstract
Familial hypercholesterolaeinia (FH) is an inherited disorder caused by
mutations in th e low-density lipoprotein (LDL) receptor which lead to
diminished clearance of cholesterol from the circulation and, consequently, to
markedly elevated LDL-cholesterol (LDL-C) levels. The resultant
hypercholesterolaem ia predisposes these patients to severe prem ature
atherosclerosis, particularly coronary artery d isease (CAD). T he concentration
of LDL-C and lifetime vascular exposure to raised plasm a LDL-C
concentrations are major determ inants of atherosclerosis, but there rem ains a
considerable variability in the extent of atherosclerosis presen t and in the
expression of clinical disease in these patients. Qualitative differences in LDL
such a s LDL particle size and susceptibility to lipid oxidation may play a role,
as may other biochemical risk factors.
The purpose of this thesis was to determine whether such qualitative
differences in LDL are important determinants of the extent and severity of
atherosclerosis and to determine whether it is mainly the reduction in LDL-C
that is of benefit, or whether antioxidant therapy would also be effective in
preventing progression of atherosclerosis in FH subjects.
FH patients were found to have large, buoyant LDL particles, which are
less susceptible to lipid oxidation than smaller, d en ser particles. In the
absence of other causes of insulin resistance, patients with FH have normal
fasting insulin and triglyceride levels, normal postprandial lipaemia, and do not
have microalbuminuria. They, therefore usually show no features of the
metabolic syndrome despite severe, accelerated atherosclerosis.
Similarly, the role of lipid oxidation in the pathogenesis of atherosclerosis in FH remains uncertain. LDL isolated from FH patients is more resistant to oxidation, and antioxidant therapy appears to be of little or no benefit in preventing progression of atherosclerosis in these hypercholesterolaem subjects. Particularly in severely hypercholesterolaem
ic subjects, m ore conclusive proof of a protective effect of
antioxidants from large prospective studies presently in progress is needed
before antioxidant therapy can be advocated for the treatm ent and prevention
of atherosclerosis.
In subjects with FH, quantitative rather than qualitative differences in
LDL are associated with accelerated atherosclerosis. Therapy in FH should
therefore be aimed primarily at reducing LDL-C levels.