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Long-Term Cardiovascular Risk in Heterozygous Familial Hypercholesterolemia Relatives Identified by Cascade Screening
Kasper Aalbæk Kjærgaard1,2, Morten Krogh Christiansen1, Morten Schmidt2
1Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark.
Insights
Relatives with heterozygous familial hypercholesterolemia and a low-density lipoprotein receptor (LDLR) mutation face increased cardiovascular event risk. This elevated risk persists despite statin therapy recommendations, highlighting a need for vigilant management.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Public Health
Background:
- Familial hypercholesterolemia (FH) is an inherited condition increasing cardiovascular disease (CVD) risk.
- The specific long-term CVD risk for relatives of FH probands with low-density lipoprotein receptor (LDLR) mutations is not well-established.
Purpose of the Study:
- To evaluate the long-term cardiovascular risk in relatives carrying an LDLR mutation, who were all recommended statin therapy.
- To compare cardiovascular risk between mutation-carrying relatives, non-mutation-carrying relatives, and the general population.
Main Methods:
- Cascade screening identified 220 relatives with a potential LDLR mutation.
- A matched cohort from the Danish general population was used for comparison.
- Participants were followed via medical registries from 1992-1994 until December 31, 2014, for major adverse cardiovascular events and all-cause mortality.
Main Results:
- Relatives with an LDLR mutation showed a 65% increased risk of major adverse cardiovascular events and all-cause mortality (aHR: 1.65) compared to the general population.
- This increased risk was observed despite 89% of mutation carriers receiving statin therapy by 2004.
- Mutation carriers had a 94% higher risk compared to non-mutation carriers (aHR: 1.94), with results driven by nonfatal events.
Conclusions:
- Heterozygous familial hypercholesterolemia relatives with an LDLR mutation experience a significantly increased long-term risk of adverse cardiovascular events.
- The findings underscore the persistent CVD risk in this population even with recommended lipid-lowering treatment.
Background:
Heterozygous familial hypercholesterolemia increases the risk of adverse cardiovascular events. Whether affected relatives of probands are at increased risk remains unknown. We aimed to evaluate the long-term cardiovascular risk in heterozygous familial hypercholesterolemia relatives with a low-density lipoprotein receptor (LDLR) mutation who were all recommended statin therapy.
Methods And Results:
Participants were identified by cascade screening at Aarhus University Hospital during 1992-1994. A comparison cohort from the Danish general population was matched 10:1 to relatives by birth year and sex. Using medical registries, participants were followed until the event of interest, migration, death, or end of follow-up on December 31, 2014. The primary end point was all-cause mortality and major adverse cardiovascular events comprising myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, and coronary revascularization. We included 220 relatives. Median age was 37 years (interquartile range: 27-52 years) of which 118 (54%) had an LDLR mutation. By 2004, when prescription data became available, 89% of mutation-carrying participants were taking statins during their follow-up period. Despite frequent use of lipid-lowering medication, the adjusted hazard ratio of the primary end point was 1.65 (95% confidence interval, 1.17-2.33) in mutation-carrying relatives compared with the general population cohort. The risk in non-mutation-carrying relatives was not different from that of the general population cohort (adjusted hazard ratio: 0.85; 95% confidence interval, 0.56-1.29). Comparing mutation-carrying relatives with non-mutation-carrying relatives, the adjusted hazard ratio was 1.94 (95% confidence interval, 1.14-3.31). Results were driven by nonfatal events.
Conclusion:
Heterozygous familial hypercholesterolemia relatives with an LDLR mutation had an increased long-term risk of adverse cardiovascular events.
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