Corresponding Author
Key words: atherosclerosis, familial hypercholesterolemia, PCSK9
Visual Summary.
Summary of Familial Hypercholesterolemia Epidemiology, Natural History, Impact of Therapy, and Undertreatment of Women
Heterozygous familial hypercholesterolemia (FH) affects 1 in 311 people in the general population.1 FH is characterized by an elevation in low-density lipoprotein (LDL) cholesterol from birth (usually >160 mg/dL in children and adolescents and >190 mg/dL in adults) and an early onset of atherosclerotic cardiovascular disease (ASCVD). FH is an autosomal dominant disease that affects men and women equally.2 Fortunately, women usually develop ASCVD events later than men due to possible estrogen protection.3 The risk of ASCVD events, however, independent of sex, may be higher in those with very high LDL cholesterol (usually >320 mg/dL), smokers, and those with high lipoprotein(a), low HDL-cholesterol, hypertension, diabetes, a high polygenic cardiovascular risk score, presence of subclinical coronary atherosclerosis, and a strong family history of early events.1,4
In addition to a healthy lifestyle, pharmacological therapy should be initiated after age 8 years to prevent atherosclerosis buildup and clinical events.5 Given the very high LDL-cholesterol concentrations typical of FH, patients often require a combination of statins, ezetimibe, and PCSK9 inhibitors to achieve the recommended LDL-cholesterol goals to mitigate ASCVD risk. Pharmacological therapy indeed prevents ASCVD events, is safe, and prolongs the lives of people affected by FH.1 However, most patients with the disease are still not diagnosed and therefore not treated. This gap is unfortunately greater in women with FH2,3 who usually have their lifetime ASCVD risk underestimated.
The 2 cases presented in this issue of JACC Case Reports by Flores-Renteria et al illustrate how late diagnosis, both patients were diagnosed only as adults, and poor cholesterol control, LDL cholesterol was still very high despite statins, may lead to early coronary disease events in young women.6 Both cases needed coronary revascularization due to the onset of acute coronary events. The cases show that despite interventional procedures to improve myocardial perfusion, reduce ischemia, and improve symptoms, atherosclerosis progressed, and ASCVD events recurred. Certainly, this occurred because of the accumulated plaque burden and the still-elevated LDL-cholesterol levels despite statin and/or ezetimibe use. Case number 2 illustrated that adding a PCSK9 inhibitor was essential to control LDL cholesterol in these patients. Both patients will need intensive LDL-cholesterol lowering for the rest of their lives. In addition to patient treatment, adequate FH management includes family cascade screening, since the disease usually affects 50% of first-degree relatives, and genetic testing to identify and treat affected asymptomatic relatives (Visual Summary).5
Currently, medicine provides the means for an adequate diagnosis and treatment of people affected by FH; however, if we do not look for it, we will find the disease when ASCVD is already putting patients' lives at risk, or even worse, when a young person dies of a preventable cause. The 2 cases described6 show the consequences of late diagnosis and inadequate management of high LDL cholesterol in 2 young women with FH. They are not isolated examples, as shown recently by Iatan et al in a recent systematic review and meta-analysis.3 Women and men with FH must be diagnosed early and treated adequately!
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Funding Support and Author Disclosures
Dr Santos is supported by a grant from the National Council for Scientific and Technological Development, Brazil (CNPq, grant number 303771/2023-2). Dr Santos is a consultant for Daiichi Sankyo, Eli-Lilly, Esperion, Novartis, Novo Nordisk, and Ultragenyx. He has received speaker honoraria from Amgen, Novo Nordisk, Novartis, Eli Lilly, Daiichi Sankyo, Torrent, and Chiesi. He has participated in trials run by Amgen, Astra-Zeneca, Novartis, Eli-Lilly, Ionis, Sanofi/Regeneron, MSD, and Arrowhead.
Footnotes
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References
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