Are there studies showing people with Familial Hypercholesterolemia (FH) do not develop premature atherosclerosis?

Familial Hypercholesterolemia and Premature Atherosclerosis: The Inevitable Connection

No studies exist demonstrating that people with Familial Hypercholesterolemia (FH) do not develop premature atherosclerosis. 1 The scientific evidence consistently shows that untreated FH leads to premature atherosclerotic cardiovascular disease due to lifelong exposure to elevated LDL-cholesterol levels from birth.

The Pathophysiology of FH and Atherosclerosis

• FH is a co-dominant and highly penetrant monogenic disorder characterized by markedly elevated LDL-cholesterol concentrations from birth, which if untreated, inevitably leads to premature atherosclerotic cardiovascular disease (ASCVD) 1
• FH results from defects in the hepatic LDL clearance pathway, most commonly involving mutations in LDLR, APOB, and PCSK9 genes, leading to impaired clearance of circulating LDL particles 1, 2
• The Pathobiological Determinants of Atherosclerosis in Youth Study (PDAY) and the Bogalusa Heart Study demonstrated that every 0.26–0.39 mmol/L (10–15 mg/dL) increase in non-HDL cholesterol is associated with an additional year of vascular aging 1
• A 15-year-old with heterozygous FH essentially has the same amount of atherosclerosis as a 20–35 year old with average lipid profile, depending on additional risk factors 1

Evidence from Genetic Studies

• Mendelian randomization studies of common DNA polymorphisms with effects on LDL cholesterol provide strong evidence for a causative role of LDL in cardiovascular disease 1
• Genetic variants at PCSK9, HMGCR, and NPC1L1 loci that specifically associate with LDL cholesterol also predict coronary heart disease risk 1
• Studies have shown that loss of function mutations in PCSK9 are associated with reduced LDL cholesterol and substantial reductions in coronary heart disease risk 1
• The prevalence of FH mutations in individuals with premature coronary artery disease is more than 15-fold higher compared to the general population 3

Clinical Presentation and Diagnosis

• FH is characterized by elevated LDL-cholesterol levels that distinguish it from other primary and secondary causes of hyperlipidemia 1
• Clinical diagnosis relies on elevated LDL-cholesterol concentrations, family history of premature coronary artery disease, and physical stigmata such as tendon xanthomas 1
• In children, clinical diagnosis depends on elevated LDL-cholesterol concentrations and a positive family history of premature coronary artery disease and/or high LDL-cholesterol concentration in at least one parent 1
• Wiegman and colleagues found that an LDL cholesterol level ≥3.5 mmol/L (135 mg/dL) predicted the presence of familial hypercholesterolemia with a 0.98 posttest probability in children from FH kindreds 1

Variable Risk Among FH Patients

• Despite the universal increased risk, cardiovascular risk varies among individuals with FH, even among those with the same genetic mutations and comparable LDL-C levels 4
• Additional cardiovascular risk modifiers beyond LDL-C may contribute to increased CVD risk in the FH population 4
• Risk factors that further exacerbate premature cardiovascular disease in FH include more extreme elevations of LDL cholesterol, elevated lipoprotein(a) levels, and decreased HDL cholesterol levels 1
• Adherence to a heart-healthy diet is associated with lower concentrations of atherogenic lipids and lipoproteins, and lower risk of ischemic heart disease in individuals with clinical FH, independent of treatment with lipid-lowering medication 5

Public Health Impact

• FH affects approximately 1 in 311 people in the general population, potentially impacting up to 35 million people worldwide 1
• Only about 10% of FH cases are currently diagnosed, and >80% of those treated do not achieve recommended LDL-cholesterol goals 1
• Early identification and treatment of FH subjects is essential to prevent or delay the onset of cardiovascular events 6
• Current guidelines recommend LDL-C targets for FH patients of <100 mg/dL (<2.6 mmol/L) for adults or <70 mg/dL (<1.8 mmol/L) for adults with CHD or diabetes, and <135 mg/dL (<3.5 mmol/L) for children 6

Clinical Implications

• Early intervention with lipid-lowering therapy is crucial for preventing premature atherosclerosis in FH patients 6
• The International Atherosclerosis Society has proposed a definition of severe FH to identify very high-risk heterozygous FH subjects according to their clinical characteristics 7
• Comprehensive risk stratification should be used to allocate appropriate intensity of lipid-lowering therapies in FH subjects, which ultimately improves cardiovascular outcomes 7
• Dietary adherence should be emphasized as an important tool in addition to treatment with lipid-lowering medication in individuals with FH 5

In summary, the scientific literature consistently demonstrates that untreated FH leads to premature atherosclerosis due to lifelong exposure to elevated LDL-cholesterol levels. No credible studies exist showing that people with FH do not develop premature atherosclerosis.