A resilient type of familial hypercholesterolaemia: case–control follow-up of genetically characterized older patients in the SAFEHEART cohort

Abstract

Aims Knowledge of the features of patients with familial hypercholesterolaemia (FH) who are protected from atherosclerotic cardiovascular disease (ASCVD) is important for the clinical and prognostic care of this apparently high-risk condition. Our aim was to investigate the determinant and characteristics of patients with FH who are protected from ASCVD and have normal life expectancy, so-called ‘resilient’ FH (R-FH). Methods and results Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART) is an open, multicentre, nation-wide, long-term prospective cohort study in genetically defined patients with heterozygous FH in Spain. Patients in the registry who at the time of analysis were at least 65 years or those who would have reached that age had they not died from an ASCVD event were analysed as a case–control study. Resilient FH was defined as the presence of a pathogenic mutation causative of FH in a patient aged ≥65 years without clinical ASCVD. Nine hundred and thirty registrants with FH met the study criteria. A defective low-density lipoprotein (LDL)-receptor mutation, higher plasma level of high-density lipoprotein cholesterol (HDL-C), younger age, female gender, absence of hypertension, and lower plasma lipoprotein (a) [Lp(a)] concentration were independently predictive of R-FH. In a second model, higher levels of HDL-C and lower 10-year score in SAFEHEART-RE were also independently predictive of R-FH. Conclusion Resilient FH may be typified as being female and having a defective LDL-receptor mutation, higher levels of plasma HDL-C, lower levels of Lp(a), and an absence of hypertension. The implications of this type of FH for clinical practice guidelines and the value for service design and optional care of FH remains to be established. Trial registration ClinicalTrials.gov number NCT02693548.

Resilient Older Subjects with Heterozygous Familial Hypercholesterolemia, Baseline Differences and Associated Factors

“…As previously detailed, resilient HeFH subjects of the present study were younger, mostly female, presented fewer comorbidities, and had higher HDL and lower Lp(a) concentrations at baseline in comparison to the ACVD group. These results fully agree with those observed in the SAFEHEART study in genetically defined patients ≥ 65 years old with HeFH diagnosis in Spain [11]. In that study [11], the resilient group profile also englobed those subjects with a younger age, female gender, absence of hypertension, elevated HDL cholesterol and decreased Lp(a) levels.…”

“…However, the possible associated factors to the cardiovascular-event free survival in these individuals have not been fully established. In this regard, a recent study [11] with HeFH subjects aged ≥ 65 years, observed that factors such as age, gender, carrying a defective mutation, presence of comorbidities and lipid subfractions were related to the presence or not of ACVD. However, further evidence on whether this resilience state is maintained over time, or if these same factors apply for resilient HeFH subjects of a more advanced age, is, at present, very scarce and inconsistent.…”

Predictors of cardiovascular risk in familial hypercholesterolemia

“…In 2022, this same group published the determinants and characteristics of patients with FH who were protected against ASCVD and had a normal life expectancy, the so-called “resilient” FH. Being female, having a defective LDL receptor mutation, higher plasma HDL-C levels, lower Lp(a) levels, and absence of hypertension were associated with this condition [14 ▪▪ ].…”

“…Risk stratification can identify patients who require treatment intensification and guide the best use of healthcare resources [13]. Male gender, late initiation of LLT, smoking, low high-density lipoprotein cholesterol (HDL-C), obesity, DM, hypertension, chronic kidney disease, and elevated lipoprotein(a) [Lp(a)] levels are independent predictors of the risk of ASCVD in patients with FH [14 ▪▪ ,15]. There is a clear need for improved assessment of sex-specific risk factors for ASCVD in women with FH, such as reproductive history.…”

Familial Hypercholesterolemia and Elevated Lipoprotein(a): Cascade Testing and Other Implications for Contextual Models of Care

“…It follows that extremely elevated Lp(a) concentrations (>95 percentiles, 100 mg/dL or 200 nmol/L) would be strongly predictive of future ASCVD in FH. Conversely, low Lp(a) levels (1–74th percentile, 0–30 mg/dL or 0–60 nmol/L) may contribute to resilience against ASCVD in FH ( Perez de Isla et al, 2021 ).…”