Background
Patients with familial hypercholesterolemia who harbored both low‐density lipoprotein receptor (
LDLR
) and
PCSK9
(proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low‐density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both
LDLR
and
PCSK9
gene variants.
Methods and Results
A total of 232 unrelated patients with
LDLR
and/or
PCSK9
gene variants were stratified as follows: patients with
LDLR
and
PCSK9
(
LDLR/PCSK9
) gene variants, patients with
LDLR
gene variant, and patients with
PCSK9
gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with
LDLR/PCSK9
gene variants were identified in 6% of study patients. They had higher levels of low‐density lipoprotein cholesterol (
P
=0.04) than those with
LDLR
gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66–11.0;
P
=0.003 versus patients with
LDLR
gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with
LDLR/PCSK9
gene variants compared with those with
LDLR
gene variant (86% versus 24%;
P
<0.001).
Conclusions
Patients with
LDLR/PCSK9
gene variants were high‐risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with
LDLR/PCSK9
gene variants, who require more stringent antiatherosclerotic management.
Low-density lipoprotein receptor gene transfer in hypercholesterolemic mice improves cardiac function after myocardial infarction
