Clinical Features and Gaps in the Management of Probable Familial Hypercholesterolemia and Cardiovascular Disease

Abstract

in order to identify insured patients with a high probability of FH. The study protocol has been reported in detail. 4 In short, inclusion in the study required peak LDL-C documented in the computerized database that was above age-dependent cut-offs associated with a high probability of FH in the general population, based on the modified MEDPED (make early diagnosis prevent early death) criteria: LDL-C >190 mg/dL in individuals <20 years of age, LDL-C >220 mg/dL at 20-29 years, and LDL-C >250 mg/dL at ≥30 years of age. 5 Patients with secondary etiologies of severe hypercholesterolemia and suspected familial combined hyperlipidemia, characterized by high triglyceride levels in addition to hypercholesterolemia with high intra-individual variability of the lipid phenotype over time, were excluded. Out of the F amilial hypercholesterolemia (FH) is a common monogenic disorder, with a prevalence of approximately 1:300 i n its heterozygous form in the general population. 1 Clinical diagnosis of FH is based on elevated age-dependent low-density lipoprotein cholesterol (LDL-C), characteristic physical stigmata, and premature atherosclerotic cardiovascular disease (ASCVD) due to lifelong exposure of the arterial vasculature to high LDL-C. Given that inheritance is primarily autosomal dominant, evidence of these signs in first-and second-degree relatives strengthens the clinical diagnosis, and gene-environment interactions modulate ASCVD risk. 2 Although much research has been done in recent years on evaluating gaps in identification, diagnosis and management of FH, data are lacking regarding the clinical manifestations of ASCVD in FH, the associated risk factors mediating the progression of atherosclerosis, and the risk of recurrent interventions and cardiovascular events. 3 In the current study we explored clinical characteristics and current needs in the management of FH patients with prevalent ASCVD, and investigated predictors of repeat coronary revascularization. Methods and Results:A regional database of 1,690 adult patients with high-probability FH based on age-dependent peak-lowdensity lipoprotein cholesterol (LDL-C) cut-offs and exclusion of secondary causes of severe hypercholesterolemia, was examined to explore the clinical manifestations and current needs in the management of ASCVD, which was present in 248 patients (15%), of whom 83% had coronary artery disease (CAD); 19%, stroke; and 13%, peripheral artery disease. ASCVD was associated with male gender, higher peak LDL-C, lower high-density lipoprotein cholesterol (HDL-C), and traditional risk factor burden. Despite highintensity statin (prescribed in 83% and combined with ezetimibe in 42%), attainment of LDL-C treatment goals was low, and associated with treatment intensity and drug adherence. Multivessel CAD (adjusted hazard ratios (HR), 3.05; 95% CI: 1.65-5.64), myocardial infarction, and the presence of ≥1 traditional risk factor (HR, 2.59; 95% CI: 1.42-4.71), were associated with repeat coronary revascularizations, in contrast with peak LDL-C >300 mg/...

Individuals with familial hypercholesterolemia and cardiovascular events have higher circulating Lp(a) levels

“…This is consistent with a previous report on 1690 individuals with clinical diagnosis of FH in which those with previous CVD events had higher classical CVD risk factors with the exception of smoking. 33 When we stratified the FH cohorts based on type of mutation (nonsense vs missense mutation), we found that individuals with nonsense mutation had an overall more severe phenotype (namely, higher total cholesterol, and LDL-C) in FH Gothenburg with similar trend in FH Milano. This is consistent with the possible presence of residual LDLR activity in missense mutations, which may mitigate the FH phenotype.…”

“…* .244 Xanthelasmas, n (%) 9 (7) 5 (13) .33 Arcus cornealis, n (%) † 27 (22) 17 (44) .008 Active smoking, n (%) 20 (16) 4 (10) .001 Hypertension, n (%) 20 (16) 13 (33) .019 Diabetes, n (%) 3 (2) 4 (10) . (28) .033…”

Leveraging Implementation Science to Address Health Disparities in Genomic Medicine: Examples from the Field

“…2019; 29 unaware that they carry genetic mutations. These rates are even lower among medically underserved populations [8][9][10][11] that historically have inadequate access to, or reduced utilization of, highquality health care. 12 These populations include racial/ethnic minority populations, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities.…”

“…12 These populations include racial/ethnic minority populations, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities. 12 Disparities in uptake of evidencebased guidelines for HBOC 10 , LS 9 and FH 8,11 have been documented and demonstrate a critical challenge in the implementation of genomic medicine.…”

“…Disparities in genomic medicine have been documented. [8][9][10][11] For example, African American women with breast cancer 10 and family history of breast or ovarian cancer 13 are less likely than White women to receive related genetic testing. Such disparities likely originate from socioeconomic and cultural factors that are associated with health care disparities more broadly.…”