Coronary artery event-free or resilient familial hypercholesterolemia: what's in a name?

Area of Science:

• Cardiovascular Medicine
• Genetics
• Metabolic Disorders

Background:

• Familial hypercholesterolemia (FH) is an autosomal semi-dominant disorder causing high LDL-C from birth, accelerating atherosclerotic cardiovascular disease (ASCVD).
• While high LDL-C is a primary driver of ASCVD in heterozygous FH (HeFH), variations in disease progression suggest other modifying factors.
• Recent research has identified an 'resilient FH' phenotype in HeFH patients who remain free of ASCVD events.

Purpose of the Study:

• To review recent evidence on the characteristics of resilient FH patients.
• To understand the factors contributing to the absence of ASCVD in a subset of HeFH individuals.
• To explore the implications of resilient FH for risk stratification and prevention strategies.

Main Methods:

• Literature review of recent evidence on resilient FH.
• Analysis of clinical features, comorbidities, and lipid profiles of resilient vs. non-resilient FH patients.
• Examination of gene expression data related to HDL metabolism and immune responses in resilient FH.

Main Results:

• Resilient FH patients are more likely female, with fewer ASCVD comorbidities, higher HDL-C, larger HDL particles, and lower lipoprotein(a).
• A lower SAFEHEART risk score independently predicts resilient FH.
• Gene expression studies show a less atherogenic profile in resilient FH, with higher ABCA1/ABCG1 and lower STAT2/STAT3 expression.

Conclusions:

• A distinct group of HeFH patients, termed resilient FH, can reach advanced ages without ASCVD events.
• Key factors contributing to event-free CAD in HeFH have been identified.
• Understanding resilient FH can enhance risk stratification and management for FH and inform primary/secondary prevention in the general population, though further research is needed.