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Abnormalities of high density lipoproteins in homozygous familial hypercholesterolemia
Insights
Low high density lipoprotein (HDL) levels are linked to atherosclerosis risk in familial hypercholesterolemia (FH). This study found reduced HDL cholesterol and apolipoproteins in FH patients, suggesting HDL
Area of Science:
- Cardiovascular Medicine
- Metabolic Disorders
- Lipid Metabolism
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by extremely high levels of low-density lipoprotein (LDL) cholesterol.
- Occlusive atherosclerosis is a major complication in FH patients, leading to premature cardiovascular disease.
- The role of low high-density lipoprotein (HDL) levels in FH pathophysiology and atherosclerosis development requires further investigation.
Purpose of the Study:
- To investigate the detailed lipid and apoprotein abnormalities in high-density lipoprotein (HDL) in patients with familial hypercholesterolemia (FH).
- To compare HDL profiles between FH homozygotes, heterozygotes, and unaffected relatives.
- To explore the relationship between reduced HDL levels and the accelerated atherosclerosis observed in FH.
Main Methods:
- Measurement of HDL lipid and apoprotein values in nine FH homozygotes.
- Comparison of HDL parameters between FH homozygotes, heterozygotes, and control subjects (unaffected relatives).
- Density gradient ultracentrifugation of serum and isolated HDL to analyze HDL subclasses (HDL2) and particle density.
Main Results:
- FH homozygotes exhibited markedly reduced HDL cholesterol, apolipoprotein A-I (apo A-I), and apolipoprotein A-II (apo A-II) levels compared to unaffected relatives.
- HDL profiles in FH heterozygotes showed intermediate abnormalities between homozygotes and controls.
- Ultracentrifugation revealed minimal to absent HDL2 and an increased peak density of HDL particles (1.15 g/ml) in FH homozygotes.
Conclusions:
- Reduced HDL levels, including diminished HDL cholesterol and apolipoproteins, are a significant feature in familial hypercholesterolemia.
- The observed HDL abnormalities in FH, particularly in homozygotes, may contribute to the increased risk and severity of occlusive atherosclerosis.
- While the exact pathophysiology linking elevated LDL and reduced HDL in FH remains unclear, these findings support the concept that HDL dysfunction plays a role in FH-related cardiovascular disease.
Abstract:
The possibility that low high density lipoprotein (HDL) levels may add to the risk of occlusive atherosclerosis in familial hypercholesterolemia (FH) is supported by the frequency and severity of this finding in these patients, particularly homozygotes. To investigate this abnormality in greater detail, we measured HDL lipid and apoprotein values in nine homozygotes with FH. Compared to their unaffected relatives, they had markedly reduced HDL cholesterol and apo A-I and A-II levels. The values found in heterozygote relatives were between those of homozygotes and those of controls. Density gradient ultracentrifugation of serum or isolated HDL from homozygotes demonstrated little or no HDL2; there was also a shift of homozygotes' HDL to an above normal peak density (d = 1.15 g/ml). Heterozygotes had milder abnormalities. The reduced HDL in FH seems to be related to elevated low density lipoprotein levels although the pathophysiology is unknown. These findings add weight to the concept that HDL abnormalities contribute to the relentless course of atherosclerosis in familial hypercholesterolemia.