First Author and Corresponding Author
Key words: genetic disorders, lipid metabolism disorders, positron emission tomography
Familial hypercholesterolemia (FH) is a common genetic condition that substantially raises atherosclerotic cardiovascular disease (ASCVD) risk. However, the risk is not uniform among all patients, even with comparable low-density lipoprotein cholesterol (LDL-C) levels or similar pathogenic mutations in the typical FH-causing genes.1 This variability is not adequately explained by traditional ASCVD risk factors and creates a challenge for risk stratification.1
Nakayoshi et al2 describe a case series involving a 71-year-old father and his 35-year-old son, both with FH. They shared a pathogenic variant in LDLR, although the son was a compound heterozygote with an additional pathogenic variant in APOB. The father had established ASCVD and was being treated with rosuvastatin, ezetimibe, and evolocumab, with an on-treatment LDL-C of 42 mg/dL. In contrast, the son had no evidence of subclinical ASCVD based on coronary computed tomography (CT) angiography. He was treated with rosuvastatin for a year along with several months of ezetimibe, with a treated LDL-C of 137 mg/dL and a higher level of oxidized LDL-C particles. Both patients had bilateral Achilles tendon xanthomas (TX) based on plain radiography and ultrasonography. However, when imaged by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), the son's Achilles tendons demonstrated intense uptake and metabolic activity, whereas the father's Achilles tendons did not demonstrate significant tracer uptake.
The authors discuss several factors that could contribute to the findings. These include the potential effects of compound heterozygosity, oxidative LDL-C levels, differences in the duration of lipid-lowering therapy and extent of LDL-C lowering, and uncertainty about the natural history of TX.2 Genetic contributions to FH phenotype extend beyond the primary FH-causative genes and also involve single-nucleotide polymorphisms that contribute to polygenic risk. Elevated polygenic risk scores for coronary artery disease can double the ASCVD risk in patients with heterozygous FH.3 Systemic inflammation is thought to represent a key pathway for the pathogenesis of ASCVD. FDG-PET imaging of arteries correlates with ASCVD risk and can help identify early disease due to the presence of activated macrophages and foam cells in the arterial wall, potentially detecting changes earlier than other traditional forms of vascular imaging such as ultrasound or coronary calcium scoring.4 Interestingly, FDG uptake and vascular calcification do not tend to overlap, suggesting that the presence of calcification may be more indicative of burnt-out inflammation.5
There is limited evidence currently regarding the use of FDG-PET in FH. In one previous trial, FDG uptake was found to be higher in the arterial wall of FH patients than in normolipidemic controls.6 The presence of Achilles TX is associated with ASCVD burden,7 and FDG-PET/CT has been described in case reports for identifying TX.8 Although not specific to an FH population, statin therapy can result in rapid reductions in tracer uptake on FDG-PET/CT of large arteries in a dose-dependent manner within a timeframe as short as 1 month.9 Statins do not consistently decrease Achilles tendon thickness in FH, but the addition of a PCSK9i has been shown to produce significant reductions in TX.10
The case series presented by the authors2 provides an interesting intergenerational comparison of FDG uptake of Achilles TX among first-degree relatives with different current clinical phenotypes. The authors point to the ability of FDG-PET/CT to detect active inflammatory processes and suggest the potential for using this as a risk-stratification tool. It highlights a need for further research into the use of FDG-PET imaging of Achilles tendon xanthoma to better understand the natural history and the potential to utilize this modality for risk stratification of younger patients with FH before the development of subclinical ASCVD. The use of FDG-PET/CT would need to be balanced with the cost, access challenges, and risks of additional radiation in young patients.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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