On the occasion of Familial Hypercholesterolemia (FH) Awareness Day, the Sant Pau Research Institute (IR Sant Pau) highlights its commitment to biomedical research aimed at improving the diagnosis and treatment of this highly prevalent genetic disease with a strong impact on cardiovascular health.
Heterozygous familial hypercholesterolemia (FH) is a genetic disorder that affects approximately 1 in 250 people. It is transmitted in an autosomal dominant manner, meaning that inheriting a single altered copy of the gene from one parent is sufficient to develop the disease. It is caused by mutations in key genes of lipid metabolism, such as LDLR, APOB, or PCSK9, which regulate how the body clears LDL cholesterol, commonly known as “bad cholesterol.”
Under normal conditions, the liver removes this cholesterol from the blood and clears it from circulation. This clearance process is essential for maintaining healthy levels. However, in individuals with FH, the clearance mechanism is impaired, leading to excessive LDL cholesterol accumulation in the blood from birth. This buildup significantly increases the risk of developing premature atherosclerotic cardiovascular disease, such as myocardial infarction or angina, at much earlier ages than in the general population—even before the age of forty.
Despite its frequency, FH remains underdiagnosed. It is estimated that fewer than 20% of cases are identified, representing a major missed prevention opportunity. Moreover, even among diagnosed patients, there are wide variations in treatment intensity and adequacy, which negatively impact long-term prognosis.
IR Sant Pau actively participates in SAFEHEART, a nationwide, prospective, multicenter cohort in Spain that conducts clinical, lipid, and genetic follow-up of individuals with FH. SAFEHEART was launched in 2004 by the Familial Hypercholesterolemia Foundation, which has since promoted, managed, and coordinated it under the leadership of Dr. Pedro Mata. With more than 4,000 genetically confirmed patients, it is the largest and best-characterized registry of this disease worldwide. Over the years, this cohort has generated numerous reference studies to better understand the natural history of FH and improve clinical management.
One of the most recent studies from this cohort has analyzed in depth the differences between men and women in lifetime burden of atherosclerotic cardiovascular disease. The analysis, involving Dr. Teresa Padró, head of the Cardiovascular Disease Evolution Biomarkers Group at IR Sant Pau and member of the CIBER of Cardiovascular Diseases (CIBERCV), aimed to determine the extent to which sex influences cardiovascular risk. It also sought to determine the age of event onset in people with FH. The results were published in The Lancet Diabetes & Endocrinology.
“Having access to such a well-characterized cohort as SAFEHEART, with over a decade of follow-up and genetically confirmed diagnoses, has allowed us for the first time to robustly analyze how sex influences the cardiovascular prognosis of these patients,” emphasized Dr. Padró.
The findings are conclusive. Over the follow-up period, women with FH showed a significantly lower risk of cardiovascular events compared to men. Moreover, when these events did occur, they did so at older ages. The mean age of onset of the first cardiovascular event was 61.6 years in women compared with 50.6 years in men. This more than decade-long difference remained even after adjusting for age, family history, traditional risk factors such as hypertension, diabetes, or smoking, as well as lipid profile and type of treatment received.
In terms of event-free survival from major cardiovascular outcomes, such as myocardial infarction, stroke, or coronary revascularization, women also fared better. While the median age of the first event in men was 55.5 years, in women this was delayed until 74.9 years. Thus, the probability of remaining free of cardiovascular disease from birth was considerably higher in the female group.
“Women not only experience fewer cardiovascular events, but these occur later in life. This forces us to reflect on the possible biological bases of this protection and, at the same time, on the biases that still exist in clinical care,” noted Dr. Padró.
Although both men and women achieved similar reductions in LDL cholesterol during follow-up, men more frequently received high-intensity statin combinations with ezetimibe or PCSK9 inhibitors, indicating differences in therapeutic strategies applied according to patient sex. Nevertheless, women with FH in the SAFEHEART cohort showed a lower incidence of coronary disease and lower cardiovascular mortality during follow-up.
These differences may be partly explained by intrinsic biological factors, such as higher HDL cholesterol levels in women, the protective effect of sex hormones before menopause, or lower overall atherosclerotic burden at younger ages.
“The combination of protective biological factors and clinical factors yet to be fully addressed should encourage us to consider more personalized treatment strategies. We cannot assume cardiovascular risk is the same for all patients with FH. Incorporating the sex perspective into clinical practice is essential,” said the IR Sant Pau researcher.
For years, IR Sant Pau has worked to promote cardiovascular medicine based on risk stratification and personalized clinical decision-making. In the case of FH, this vision involves not only early detection of carriers of pathogenic genetic mutations but also tailoring treatment to each patient’s individual profile, considering clinical, biological, and social characteristics, including sex.
IR Sant Pau’s contribution to the SAFEHEART cohort reinforces the institution’s commitment to translational research that directly impacts clinical practice and public health. Through multidisciplinary teams, collaborative networks, and a comprehensive approach to patient care, the center contributes to advancing knowledge, management, and prognosis of preventable cardiovascular diseases.
“Our goal as researchers is that no patient with FH goes unidentified and untreated. At the same time, we aim to ensure that treatment is the most appropriate for each individual. This is the foundation of medicine that is fairer, more effective, and more humane,” concluded Dr. Padró.
de Isla LP, Vallejo-Vaz AJ, Watts GF, Muñiz-Grijalvo O, Alonso R, Diaz-Diaz JL, Arroyo-Olivares R, Aguado R, Argueso R, Mauri M, Romero MJ, Álvarez-Baños P, Mañas D, Cepeda JM, Gonzalez-Bustos P, Casañas M, Michan A, Muñoz-Torrero JFS, Faedo C, Barba MA, Dieguez M, de Andrés R, Hernandez AM, Gonzalez-Estrada A, Padró T, Fuentes F, Badimon L, Mata P, SAFEHEART Investigators. Long-term sex differences in atherosclerotic cardiovascular disease in individuals with heterozygous familial hypercholesterolaemia in Spain: a study using data from SAFEHEART, a nationwide, multicentre, prospective cohort study. Lancet Diabetes Endocrinol 2024;12:643–52. https://doi.org/10.1016/S2213-8587(24)00192-X
